Thiazolidine derivatives, their preparation and use

ABSTRACT

Compounds of formula (I):   &lt;IMAGE&gt; (I)  (in which R1-R7 are hydrogen or various organic groups, n is 1-10, Ar is an aromatic group, U is CH2 or a carbon atom doubly bonded to either one of its adjacent carbons, and W is &gt;CH2, &gt;C=O, &gt;CHOH, &gt;C=NOH or various derivatives thereof) have the ability to lower the levels of blood lipid peroxides and blood sugars and to inhibit the activity of aldose reductase; they may be used therapeutically for these purposes.

This application is a Continuation, of application Ser. No. 07/426,533,filed Oct. 24, 1989 now abandoned, which is a continuation of Ser. No.07/311,445 filed Feb. 15, 1989 (abandoned); which is a continuation ofSer. No. 07/233,984 filed Aug. 11, 1988 (abandoned); which is acontinuation of Ser. No. 06/833,867 filed Feb. 25, 1986 (abandoned).

BACKGROUND TO THE INVENTION

The present invention relates to a series of novel thiazolidinederivatives containing, on a side chain attached to the 5-position, achroman ring system. The invention also provides processes for preparingthese compounds and compositions and methods for using them, especiallyfor reducing blood lipid and blood sugar levels.

Certain thiazolidine derivatives having the ability to lower blood lipidand blood sugar levels are disclosed in European Patent Publication No.8203 and in Chem. Pharm. Bull., 30, 3580 (1982). Certain of thethiazolidine derivatives disclosed in these documents have the abilityto lower blood lipid and blood sugar levels, although these compoundsare rather toxic.

In copending U.S. patent application Ser. No. 644,996, filed Aug. 28,1984, the disclosure of which is incorporated herein by reference, thereare also disclosed some related thiazolidine derivatives having asimilar class of activities; some of these prior compounds may also beused as starting materials to prepare the compounds of the invention

We have now discovered a series of thiazolidine derivatives which havethe ability to improve the metabolism of blood lipids, that is to saythey reduce the level of blood lipid peroxides, blood triglycerides,blood cholesterol and blood sugar, whilst having a very low toxicity.The compounds of the invention also have the ability to inhibit theactivity of aldose reductase.

BRIEF SUMMARY OF INVENTION

The compounds of the present invention may be represented by the formula(I): ##STR2## in which: R¹ represents a hydrogen atom, a C₁ -C₁₀ alkylgroup or a C₇ -C₁₃ aralkyl group;

R² represents a hydrogen atom or a C₁ -C₅ alkyl group;

R³ represents a hydrogen atom, a C₁ -C₂₃ alkanoyl group, a C₃ -C₂₃alkenoyl group, a C₃ -C₂₃ alkynoyl group, a substituted C₁ -C₂₃alkanoyl, C₃ -C₂₃ alkenoyl or C₃ -C₂₃ alkynoyl group having at least onesubstituent selected from the group consisting of substituents (a), anaromatic acyl group, a heterocyclic acyl group, a group of formula --SO₃R⁸ where

R⁸ represents a hydrogen atom, an aralkyl group where the alkyl part isC₁ -C₃ alkyl, a C₁ -C₅ alkyl group or a C₁ -C₅ alkyl group having atleast one substituent selected from the group consisting of hydroxygroups and C₁ -C₅ alkoxy groups,

a C₁ -C₁₀ alkyl group or a substituted C₁ -C₁₀ alkyl group having atleast one substituent selected from the group consisting of substituents(b);

R⁴ represents a hydrogen atom, C₁ -C₁₀ alkyl group or a C₁ -C₅ alkoxygroup;

R⁵ represents a hydrogen atom, a C₁ -C₅ alkyl group or a C₁ -C₅ alkoxygroup;

R⁶ and R⁷ are independently selected from the group consisting ofhydrogen atoms, C₁ -C₁₀ alkyl groups and substituted C₁ -C₁₀ alkylgroups having at least one substituent selected from the groupconsisting of substituents (b);

Ar is a divalent group selected from the group consisting of divalentcarbocyclic aromatic groups and divalent heterocyclic aromatic groups;

W represents a --CH₂ -- group, a >C═O group, a group of formula>CH--OR¹¹

wherein R¹¹ represents a hydrogen atom, a C₁ -C₂₃ alkanoyl group, a C₃-C₂₃ alkenoyl group, a C₃ -C₂₃ alkynoyl group, a substituted C₁ -C₂₃alkanoyl, C₃ -C₂₃ alkenoyl or C₃ -C₂₃ alkynoyl group having at least onesubstituent selected from the group consisting of substituents (a), anaromatic acyl group, a heterocyclic acyl group, a C₁ -C₁₀ alkyl group ora substituted C₁ -C₁₀ alkyl group having at least one substituentselected from the group consisting of substituents (b),

or a group of formula >C═N--O--R¹²

in which R¹² represents a hydrogen atom, a C₁ -C₁₀ alkyl group, a C₁-C₁₀ alkyl group having at least one substituent selected from the groupconsisting of substituents (b), a C₁ -C₂₃ alkanoyl group, a C₃ -C₂₃alkenoyl group, a C₃ -C₂₃ alkynoyl group, a substituted C₁ -C₂₃alkanoyl, C₃ -C₂₃ alkenoyl or C₃ -C₂₃ alkynoyl group having at least onesubstituent selected from the group consisting of substituents (a), anaromatic acyl group or a heterocyclic acyl group;

U represents a --CH₂ -- group; or

W and U together represent a group of formula --CH═CH--; or

when W represents a carbonyl group or said group of formula >C═N--OR¹²,U, R¹ and the carbon atom to which R¹ is attached together represent agroup of formula --CH ═C<;

n is an integer of from 1 to 3;

said aryl groups and the aryl parts of said aralkyl, aralkyloxycarbonyl,aromatic acyl, aromatic acyloxy and divalent aromatic groups being C₆-C₁₀ carbocyclic aryl groups which are unsubstituted or have at leastone substituent selected from the group consisting of substituents (c);

said heterocyclic groups, heterocyclic parts of said heterocyclic acyland acyloxy groups and said divalent heterocyclic aromatic groups havefrom 5 to 10 ring atoms, of which from 1 to 5 are hetero-atoms selectedfrom the group consisting of nitrogen, oxygen and sulfur hetero-atoms,said heterocyclic groups being unsubstituted or having at least onesubstituent selected from the group consisting of substituents (d);

said substituents (a) being selected from the group consisting of arylgroups, carboxy groups, C₂ -C₆ alkoxycarbonyl groups andaralkyloxycarbonyl groups;

said substituents (b) being selected from the group consisting ofhydroxy groups, C₁ -C₅ alkoxy groups, aryl groups, C₁ -C₂₃ alkanoyloxygroups, C₃ -C₂₃ alkenoyloxy groups, C₃ -C₂₃ alkynoyloxy groups,substituted C₁ -C₂₃ alkanoyloxy, C₃ -C₂₃ alkenoyloxy or C₃ -C₂₃alkynoyloxy groups having at least one substitutent selected from thegroup consisting of substituents (a), aromatic acyloxy groups,heterocyclic acyloxy groups, groups of formula --COOR⁸ where R⁸ is asdefined above and groups of formula --CONR⁹ R¹⁰ where

R⁹ and R¹⁰ are independently selected from the group consisting ofhydrogen atoms and C₁ -C₅ alkyl groups or R⁹ and R¹⁰, together with thenitrogen atom to which they are attached, represent a heterocyclic grouphaving from 5 to 7 ring atoms of which from 1 to 3 atoms, including saidnitrogen atom, are hetero-atoms selected from the group consisting ofnitrogen, oxygen and sulfur hetero-atoms, said heterocyclic group beingunsubstituted, or, where said ring atoms include an additional nitrogenhetero-atom, said additional nitrogen atom being unsubstituted or havinga single substituent selected from the group consisting of substituents(e);

said substituents (c) being selected from the group consisting of C₁ -C₅alkyl groups, C₁ -C₅ alkoxy groups, C₁ -C₅ alkyl groups having at leastone halogen substituent, halogen atoms, amino groups, C₁ -C₅ alkylaminogroups, dialkylamino groups in which each alkyl part is C₁ -C₅, nitrogroups, cyano groups, groups of formula --CONR₂ where R represents a C₁-C₅ alkyl group or an aryl group and hydroxy groups; and

said substituents (d) being selected from the group consisting of C₁ -C₅alkyl groups, C₁ -C₅ alkoxy groups and doubly bonded oxygen atoms;

said substituents (e) being selected from the group consisting of C₁ -C₅alkyl groups, C₁ -C₅ alkanoyl groups, C₃ -C₅ alkenoyl groups and C₃ -C₅alkynoyl groups; provided that:

(α) where: R³ represents said hydrogen atom, an unsubstituted C₁ -C₆alkanoyl group, an unsubstituted C₃ -C₆ alkenoyl group, an unsubstitutedC₃ -C₆ alkynoyl group, said aromatic acyl group, said heterocyclic acylgroup, an aralkanoyl group or an aralkenoyl group; and R⁶ and R⁷ bothrepresent hydrogen atoms; and Ar represents a p-phenylene group; and Wrepresents a group of formula >CH₂, >C═O or >CH--OR^(11x) (whereinR^(11x) represents a hydrogen atom, an unsubstituted C₁ -C₆ alkanoylgroup, an unsubstituted C₃ -C₆ alkenoyl group, an unsubstituted C₃ -C₆alkynoyl group, said aromatic acyl group, said heterocyclic acyl group,an aralkanoyl group or an aralkenoyl group); and U represents said groupof formula >CH₂, then

(i) when R¹ represents a hydrogen atom or a C₁ -C₅ alkyl group, R⁴represents a C₆ -C₁₀ alkyl group, and

(ii) when R⁴ represents a hydrogen atom, a C₁ -C₅ alkyl group or a C₁-C₅ alkoxy group, R¹ represents a C₆ -C₁₀ alkyl group or said C₇ -C₁₃aralkyl group; or

(β) where: R¹ and R² are independently selected from the groupconsisting of hydrogen atoms and C₁ -C₅ alkyl groups; and R⁴ and R⁵ areindependently selected from the group consisting of hydrogen atoms, C₁-C₅ alkyl groups and C₁ -C₅ alkoxy groups; and Ar represents ap-phenylene group; and W is a group of formula >CH₂, >C═O or>CH--OR^(11x) (where R^(11x) is as defined above); and U represents saidgroup of formula >CH₂ ; and n is an integer from 1 to 3, then

at least one of R³, R⁶ and R⁷ represents said alkyl or substituted alkylgroup;

and pharmaceutically acceptable salts thereof.

The invention also provides processes for preparing the compounds of theinvention, as described in more detail hereafter.

The invention still further provides a pharmaceutical compositioncomprising a compound of formula (I) or a pharmaceutically acceptablesalt thereof in admixture with a pharmaceutically acceptable carrier ordiluent.

The invention still further provides a method of reducing blood lipidand blood sugar levels in an animal, especially a mammal, e.g. a humanbeing, by administering to said animal an effective amount of a compoundof formula (I) or a pharmaceutically acceptable salt thereof.

DETAILED DESCRIPTION OF INVENTION

In the compounds of the invention, where R¹, R³, R⁶, R⁷, R¹¹ or R¹²represents a C₁ -C₁₀ alkyl group, this may be a straight or branchedchain group and examples include the methyl, ethyl, propyl, isopropyl,butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, 2-methylbutyl,1-ethylpropyl, hexyl, isohexyl, neohexyl, 1-methylpentyl,3-methylpentyl, 1,1-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl,1-methyl-1-ethylpropyl, heptyl, 1-methylhexyl, 1-propylbutyl,4,4-dimethylpentyl, octyl, 1-methylheptyl, 2-ethylhexyl,5,5-dimethylhexyl, nonyl, decyl, 1-methylnonyl, 3,7-dimethyloctyl and7,7-dimethyloctyl groups.

Where R¹ or R⁸ represents an aralkyl group, this may be substituted orunsubstituted and is a C₇ -C₁₃ aralkyl group, for example substituted orunsubstituted benzyl, phenethyl, 3-phenylpropyl or 4-phenylbutyl groups.Examples of suitable substituents include: C₁ -C₄ alkyl groups,particularly the methyl, ethyl and propyl groups; C₁ -C₄ alkoxy groups,particularly the methoxy, ethoxy and propoxy groups; and halogen atoms,such as the fluorine, chlorine, bromine and iodine atoms.

Where R² represents an alkyl group, this may be a C₁ -C₅ alkyl group,for example a methyl, ethyl, propyl, isopropyl, butyl, isobutyl orpentyl group.

Where the acyl group represented by R³, R¹¹ or R¹² is an aliphatic acylgroup, this may be a saturated or unsaturated group (the terms"saturated" and "unsaturated" referring to the carbon-carbon bonds)having up to 23 carbon atoms and is thus a C₁ -C₂₃ alkanoyl, C₃ -C₂₃alkenoyl or C₃ -C₂₃ alkynoyl group, which may be unsubstituted or mayhave one or more substituents selected from substituents (a), forexample selected from the group consisting of aryl groups, carboxygroups, C₂ -C₆ alkoxycarbonyl groups or aralkyloxycarbonyl groups.Examples of such aliphatic acyl groups include the formyl, acetyl,propionyl, propiolyl, butyryl, isobutyryl, pivaloyl, hexanoyl, acryloyl,methacryloyl, crotonoyl, octanoyl, decanoyl, tridecanoyl, pentadecanoyl,hexadecanoyl, heptadecanoyl, octadecanoyl, nonadecanoyl,2,6,10,14-tetramethylnonadecanoyl and icosanoyl groups. Such groups maybe unsubstituted or have one or more (preferably one) substituents asdefined above. Suitable aryl substituents include the phenyl and 1- or2-naphthyl groups, especially the phenyl group, which may themselves beunsubstituted or have one or more substituents selected fromsubstituents (c), especially C₁ -C₅ alkyl groups, C₁ -C₅ alkoxy groups,halogen atoms, hydroxy groups, nitro groups, amino groups anddialkylamino groups where each alkyl part is C₁ -C₅ ; specific examplesof the resulting araliphatic acyl groups are given hereafter. Suitablealkoxycarbonyl groups (as substituents on these acyl groups) includestraight or branched chain C_(C) ₂ -C₆ groups (i.e. the alkoxy part isC₁ -C₅), such as the methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl,sec-butoxycarbonyl, t-butoxycarbonyl, pentyloxycarbonyl andisopentyloxycarbonyl groups. Suitable aralkyloxycarbonyl groups includethose where the aralkyl part is as exemplified above in relation to R¹.

Examples of the alkanoyl, alkenoyl and alkynoyl groups which may beincluded in substituents (e) are those unsubstituted acyl groupsexemplified above and having up to 5 carbon atoms.

Where R³, R¹¹ or R¹² represents an aromatic acyl group, this ispreferably an arylcarbonyl group in which the aryl part is as definedabove, but is preferably a phenyl or naphthyl (1- or 2-naphthyl) group,which may be unsubstituted or may have one or more of the substituents(c) defined above. Examples of such aromatic acyl groups include thebenzoyl, 4-nitrobenzoyl, 3-fluorobenzoyl, 2-chlorobenzoyl,4-aminobenzoyl, 3-dimethylaminobenzoyl, 2-methoxybenzoyl,3,4-dichlorobenzoyl, 3,5-di-t-butyl-4-hydroxybenzoyl and 1-naphthoylgroups.

Where R³, R¹¹ or R¹² represents a heterocyclic acyl group, this ispreferably a heterocyclic-carbonyl group, in which the heterocyclic partis as defined above, but is preferably a heterocyclic group having from5 to 8, and more preferably 5 or 6, ring atoms, of which from 1 to 3,and preferably 1, are hetero-atoms selected from the group consisting ofnitrogen, oxygen and sulfur hetero-atoms. Such heterocyclic groups maybe unsubstituted or may have at least one substituent (d), as definedabove. Examples of such heterocyclic acyl groups include the 2-furoyl,3-thenoyl, 3-pyridinecarbonyl and 4-pyridinecarbonyl groups.

Where R³, R¹¹ or R¹² represents an araliphatic acyl group, this ispreferably an aralkanoyl or aralkenoyl group, in which the aryl part isas defined above, but is preferably a phenyl or naphthyl group, morepreferably a phenyl group, which may be unsubstituted or may have one ormore of the substituents (c) defined above. The alkanoyl or alkenoylpart is preferably a C₂ -C₆ alkanoyl or C₃ -C₆ alkenoyl group, morepreferably an acetyl, propionyl or acryloyl group. Examples of sucharaliphatic acyl groups include the phenylacetyl,α-(4-chlorophenyl)acetyl, 3-phenylpropionyl and cinnamoyl groups.

Where R³, R⁶, R⁷, R¹¹ or R¹² represents a substituted alkyl group, thisis a C₁ -C₁₀ alkyl group having at least one of the substituents definedabove as substituents (b). The parent alkyl group may be any one ofthose exemplified above. Examples of the substituents include:

hydroxy groups;

alkanoyloxy, alkenoyloxy and alkynoyloxy groups (which may besubstituted or unsubstituted), aromatic acyloxy groups and heterocyclicacyloxy groups, examples of which are the acyloxy groups correspondingto the acyl groups exemplified above in relation to R³, R¹¹ and R¹² ;

carboxy groups (i.e. --COOR⁸ where R⁸ is hydrogen);

aralkyloxycarbonyl groups (i.e. --COOR⁸ where R⁸ is aralkyl), e.g. wherethe aralkyl part is as exemplified above in relation to R¹ ;

C₂ -C₆ alkoxycarbonyl groups (i.e. --COOR⁸ where R⁸ is C₁ -C₅ alkyl)e.g. as exemplified above in relation to substituents on aliphatic acylgroups represented by R³, R¹¹ and R¹² ;

C₂ -C₆ hydroxyalkoxycarbonyl groups (i.e. --COOR⁸ where R⁸ is C₁ -C₅hydroxyalkyl), e.g. hydroxy-substituted analogs of the alkoxycarbonylgroups mentioned above, especially 2-hydroxyethoxycarbonyl,3-hydroxypropoxycarbonyl and 2-hydroxypropoxycarbonyl groups;

alkoxyalkoxycarbonyl groups (i.e. --COOR⁸ where R⁸ is C₁ -C₅ alkylhaving a C₁ -C₅ alkoxy substituent), e.g. alkoxy-substituted analogs ofthe alkoxycarbonyl groups mentioned above, especiallymethoxymethoxycarbonyl, ethoxymethoxycarbonyl, 2-methoxyethoxycarbonyl,2-ethoxyethoxycarbonyl, 2-propoxyethoxycarbonyl,1-methoxyethoxycarbonyl, 3-methoxypropoxycarbonyl,3-ethoxypropoxycarbonyl, 3-propoxypropoxycarbonyl,3-butoxypropoxycarbonyl, 2-methoxy-1-methylethoxycarbonyl,2-ethoxy-1-methylethoxycarbonyl, 3-isopropoxypropoxycarbonyl,4-methoxybutoxycarbonyl, 4-ethoxybutoxycarbonyl,4-propoxybutoxycarbonyl, 4-butoxybutoxycarbonyl,4-t-butoxybutoxycarbonyl, 5-methoxypentyloxycarbonyl and5-ethoxypentyloxycarbonyl groups;

carbamoyl groups (i.e. --CONR⁹ R¹⁰ where R⁹ ═R¹⁰ ═H);

mono- and di- alkylcarbamoyl groups (i.e. the groups --CONR⁹ R¹⁰ whereone or both of R⁹ and R¹⁰ represents a C₁ -C₅ alkyl group), e.g. themethylcarbamoyl, ethylcarbamoyl, propylcarbamoyl, isopropylcarbamoyl,butylcarbamoyl, sec-butylcarbamoyl, pentylcarbamoyl, isopentylcarbamoyl,dimethylcarbamoyl, diethylcarbamoyl, dipropylcarbamoyl,dibutylcarbamoyl, dipentylcarbamoyl, N-methyl-N-ethylcarbamoyl,N-methyl-N-propylcarbamoyl and N-ethyl-N-propylcarbamoyl groups; and

nitrogen-containing heterocyclic acyl groups (i.e. --CONR⁹ R¹⁰ where R⁹,R¹⁰ and the nitrogen atom together form an optionally substitutedheterocyclic group), for example the 1-pyrrolylcarbonyl,1-imidazolylcarbonyl, 3-thiazolidinylcarbonyl, 1-pyrrolidinylcarbonyl,1-pyrrolinylcarbonyl, 1-imidazolinylcarbonyl, 1-imidazolidinylcarbonyl,3-methyl-1-imidazolidinylcarbonyl, 3-ethyl-1-imidazolidinylcarbonyl,3-t-butyl-1-imidazolidinylcarbonyl, 3-acetyl-1-imidazolidinylcarbonyl,3-butyryl-1-imidazolidinylcarbonyl, 3valeryl-1-imidazolidinylcarbonyl,3-pivaloyl-1-imidazolidinylcarbonyl, piperidinocarbonyl,1-piperazinylcarbonyl, 4-methyl-1-piperazinylcarbonyl,4-ethyl-1-piperazinylcarbonyl, 4-propyl-1-piperazinylcarbonyl,4-butyl-1-piperazinylcarbonyl, 4-pentyl-1-piperazinylcarbonyl,4-t-butyl-1-piperazinylcarbonyl, 4-acetyl-1-piperazinylcarbonyl,4-formyl-1-piperazinylcarbonyl, 4-propionyl-1-piperazinylcarbonyl,4-acryloyl-1-piperazinylcarbonyl, 4-methacryloyl-1-piperazinylcarbonyl,4-propioloyl-1-piperazinylcarbonyl, 4-butyryl-1-piperazinylcarbonyl,4-isovaleryl-1-piperazinylcarbonyl and morpholinocarbonyl groups.

Where R⁴ represents an alkyl group, this has from 1 to 10 carbon atomsand is a straight or branched chain group. Certain examples of suchalkyl groups have been given above in relation to such groups which maybe represented by R¹. However, preferred examples of alkyl groups whichmay be represented by R⁴ include the methyl, ethyl, propyl, isopropyl,butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, t-pentyl, hexyl,1,1-dimethylbutyl, 1,3-dimethylbutyl, heptyl, 1,1-diethylpropyl, octyl,1-methylheptyl, 2-ethylhexyl, 1,1,3,3-tetramethylbutyl, nonyl, decyl and3,7-dimethyloctyl groups.

Where R⁴, R⁵ or substituent (b) represents an alkoxy group, this mayhave from 1 to 5 carbon atoms and may be a straight or branched chaingroup. Examples of such alkoxy groups include the methoxy, ethoxy,propoxy, isopropoxy, butoxy, t-butoxy and pentyloxy groups.

Where R⁵ or substituent (e) represents an alkyl group, this may havefrom 1 to 5 carbon atoms and may be a straight or branched chain group.Examples of such alkyl groups which may be represented by R⁵ areincluded amongst the alkyl groups which may be represented by R¹ or byR⁴. However, preferred alkyl groups which may be represented by R⁵include the methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyland isopentyl groups.

Where Ar represents a divalent carbocyclic aromatic group, this may besubstituted or unsubstituted and has from 6 to 10 ring carbon atoms.Examples of such divalent aromatic groups include the p-phenylene,o-phenylene and m-phenylene groups. Where such a group is substituted,it may have at least one of the substituents (c) defined above, butpreferably C₁ -C₅ alkyl groups (e.g. the methyl, ethyl, propyl,isopropyl, butyl or pentyl groups) or C₁ -C₅ alkoxy groups (e.g. themethoxy, ethoxy, isopropoxy, t-butoxy or pentyloxy groups).

Where Ar represents a divalent aromatic heterocyclic group, theheterocyclic group is preferably a pyridine, furan, thiophene or pyrrolering, which may be unsubstituted or have at least one of thesubstituents (d) defined above, and the two free valences may be in avariety of positions. Specific examples of such groups are as follows,in which the first number given denotes the position of attachment ofthe heterocyclic group to the group of formula --(CH₂)_(n) --O--, whilstthe second number given denotes the position of attachment of theheterocyclic group to the --CH₂ -thiazolidine group; the pyrid-2,3-diyl,pyrid-2,4-diyl, pyrid-2,5-diyl, pyrid-2,6-diyl, pyrid-3,4-diyl,pyrid-3,5-diyl, pyrid-3,6-diyl, pyrid-3,2-diyl, pyrid-4,3-diyl,pyrid-4,2-diyl, furan-2,3-diyl, furan-2,4-diyl, furan-2,5-diyl,furan-3,2-diyl, furan-4,2-diyl, thien-2,3-diyl, thien-2,4-diyl,thien-2,5-diyl, thien-3,2-diyl, thien-4,2-diyl, pyrrol-2,3-diyl,pyrrol-2,4-diyl, pyrrol-2,5-diyl, pyrrol-3,2-diyl or pyrrol-4,2-diylgroups. Such groups may be unsubstituted or, if desired, may have atleast one, and preferably only one, substituted selected from thosesubstituents (d) defined above, but preferably C₁ -C₆ alkyl groups (e.g.the methyl, ethyl, isopropyl, t-butyl or pentyl groups) or C₁ -C₆ alkoxygroups (e.g. the methoxy, ethoxy, isopropoxy, t-butoxy or pentyloxygroups).

W may represent a methylene (--CH₂ --) group, a carbonyl (>C═O) group, agroup of formula >CH--OR¹¹ (in which R¹¹ is as defined above) or a groupof formula >C═NOR¹² (where R¹² is as defined above and may be the sameas or different from the atom or group represented by R³). Examples ofthe acyl and alkyl groups which may be represented by R¹¹ and R¹² are asgiven above. Where R¹² represents a group of formula --CONR⁹ R¹⁰, i.e. acarbamoyl or mono- or di-alkylcarbamoyl group, examples of such groupsare as given in relation to the similar groups which may be representedby substituents (b).

Alternatively, W and U may together form a double bond, e.g. asillustrated by the compounds of formula (I-12) described hereafter.

U preferably represents a methylene group. However, as mentioned above,it may form a double bond with W, or, when W represents a carbonyl groupor a group of formula >C═N--OR¹², U may, together with R¹ and the carbonatom to which the group represented by R¹ is attached, form a group offormula --CH═C>, e.g. as illustrated in the compounds of formulae (I-8)to (I-11), defined hereafter.

Where substituent (c) is a C₁ -C₅ alkyl group having at least onehalogen substituent, the alkyl part may be any one of those C₁ -C₅ alkylgroups defined above in relation to R⁵, both straight and branched chaingroups. The resulting haloalkyl group may have one or more halogen atoms(e.g. fluorine, chlorine, bromine or iodine atoms) up to completeperhalogenation. Examples of such groups include the chloromethyl,dichloromethyl, iodomethyl, bromethyl, fluoromethyl, trifluoromethyl,2-chloroethyl, 2-bromoethyl, 2-iodoethyl, 2-fluoroethyl,1,2-dibromoethyl, 1,2-dichloroethyl, 2,2-dichloroethyl,2,2-difluoroethyl, 2,2,2-trichloroethyl, 2,2,2-trifluoroethyl,2,2,2-tribromoethyl, 1,2,2-trichloroethyl, 1,2,3-trichloropropyl,4-chlorobutyl and 5-fluoropentyl groups, of which the trifluoromethylgroup is preferred.

Where the compounds of the present invention contain an acidic group intheir molecule, for example where they contain a carboxy group or whereR³ represents a hydrogen atom and the resulting hydroxy group is of anacidic character or where R³ represents a sulfo (--SO₃ H) group, thenthe compounds of the invention may form salts with cations. There is nolimitation upon the nature of such salts, provided that, where they areto be used for therapeutic purposes, they are pharmaceuticallyacceptable, which, as is well-known in the art, means that they do nothave reduced activity (or unacceptably reduced activity) or increasedtoxicity (or unacceptably increased toxicity) compared with the freecompound of formula (I). Where, however, they are to be used fornon-therapeutic purposes, e.g. as intermediates in the preparation ofother compounds, even this limitation does not apply. Suitable saltsinclude, for example: alkali metal salts, such as the sodium orpotassium salts; alkaline earth metal salts, such as the calcium ormagnesium salts; other metal salts, such as the aluminum or iron salts;salts with basic amino acids, such as the lysine or arginine salts;ammonium salts; and salts with organic amines, such as thecyclohexylammonium, diisopropylammonium and triethylammonium salts.

The compounds of the invention may also, depending upon the particularsubstituents, contain basic groups in their molecules and, in such acase, they can also form acid addition salts. As with the saltsmentioned above, there is no particular limitation on the nature of theacid forming such a salt, provided that, where the compound is to beused for therapeutic purposes, the resulting salt is pharmaceuticallyacceptable. Examples of suitable acids include: inorganic acids, such ashydrochloric acid, sulfuric acid, nitric acid or phosphoric acid;organic carboxylic acids, such as acetic acid, tartaric acid, maleicacid, fumaric acid, malic acid, glutamic acid or aspartic acid; andorganic sulfonic acids, such as p-toluenesulfonic acid ormethanesulfonic acid.

Preferred classes of compound of the present invention are as follows:

(1) Compounds of formula (I) in which:

R¹ represents a hydrogen atom or a C₁ -C₁₀ alkyl group;

R² represents a hydrogen atom or a C₁ -C₃ alkyl group;

R³ represents a hydrogen atom, a sulfo group, a C₁ -C₁₀ alkanoyl group,a C₃ -C₁₀ alkenoyl group, a substituted C₁ -C₁₀ alkanoyl or C₃ -C₁₀alkenoyl group having at least one substituent selected from the groupconsisting of substituents (f), an arylcarbonyl group wherein the arylpart is a C₆ -C₁₀ carbocyclic aryl group which is unsubstituted or hasat least one substituent selected from the group consisting ofsubstituents (g), a group of formula R¹³ --(CH₂)_(m) --CO--, where

R¹³ represents a phenyl group or a phenyl group having at least onesubstituent selected from the group consisting of substituents (g), andm is an integer from 1 to 5,

a group of formula Het--CO--, where

Het represents a heterocyclic group having 5 or 6 ring atoms, of whichfrom 1 to 3, and preferably 1, are hetero-atoms selected from the groupconsisting of nitrogen, oxygen and sulfur hetero-atoms, saidheterocyclic group being unsubstituted or having at least onesubstituent selected from the group consisting of C₁ -C₅ alkyl groups,

a C₁ -C₅ alkyl group substituted by a group of formula --COOR^(8a),where

R^(8a) represents a hydrogen atom, C₁ -C₅ alkyl group or an alkoxyalkylgroup where both the alkoxy part and the alkyl part are C₁ -C₅,

a C₂ -C₅ hydroxyalkyl group, an alkoxyalkyl group where both the alkoxypart and the alkyl part are C₁ -C₅, a C₂ -C₅ alkyl group substituted bya group of formula --O--CO--R⁵³, where

R⁵³ represents a C₁ -C₁₀ alkyl group, a phenyl group, a phenyl grouphaving at least one substituent selected from the group consisting ofsubstituents (g) or a heterocyclic group Het, as defined above,

or a C₁ -C₃ alkyl group substituted by a single substituent selectedfrom the group consisting of substituents (h);

said substituents (f) are selected from the group consisting of phenylgroups, carboxy groups, C₂ -C₆ alkoxycarbonyl groups andbenzyloxycarbonyl groups;

said substituents (g) are selected from the group consisting of C₁ -C₅alkyl groups, trifluoromethyl groups, C₁ -C₅ alkoxy groups, halogenatoms, nitro groups, amino groups, hydroxy groups and dialkylaminogroups where each alkyl part is C₁ -C₅ ;

said substituents (h) are selected from the group consisting ofalkylcarbamoyl groups where the alkyl part is C₁ -C₄, dialkylcarbamoylgroups where each alkyl part is C₁ -C₄, 1-pyrrolidinylcarbonyl groups,piperidinocarbonyl groups and morpholinocarbonyl groups;

R⁴ represents a C₁ -C₁₀ alkyl group or a methoxy group;

R⁵ represents a hydrogen atom, a C₁ -C₅ alkyl group or a methoxy group;

R⁶ and R⁷ are independently selected from the group consisting ofhydrogen atoms, C₁ -C₅ alkyl groups,

C₁ -C₅ alkyl groups substituted by a group of formula --COOR^(8a) whereR^(8a) is as defined above, C₂ -C₅ hydroxyalkyl groups, C₁ -C₅ alkylgroups substituted by a C₁ -C₅ alkoxy group, C₂ -C₅ alkyl groupssubstituted by a group of formula --O--CO--R⁵³ where R⁵³ is as definedabove, and C₁ -C₃ alkyl groups having a single substituent selected fromthe group consisting of substituents (h);

Ar represents a o-phenylene, m-phenylene or p-phenylene group or apyridine-diyl group which is attached to the part of said compound offormula (I) of formula --(CH₂)_(n) --O-- at its 2-position and isattached to the --CH₂ -thiazolidine group at its 5- or 6-position, saidphenylene and pyridine-diyl groups being unsubstituted or having a C₁-C₃ alkyl substituent;

W represents a group of formula --CH₂ --, >C═O, >CH--OR¹¹ or >C═N--OR¹²where

R¹¹ represents a hydrogen atom, a C₁ -C₁₀ alkanoyl group (preferably anacetyl group), a C₃ -C₁₀ alkenoyl group, a substituted C₁ -C₁₀ alkanoylor C₃ -C₁₀ alkenoyl group having at least one substituent selected fromthe group consisting of substituents (f), an arylcarbonyl group whereinthe aryl part is a C₆ -C₁₀ carbocyclic aryl group which is unsubstitutedor has at least one substituent selected from the group consisting ofsubstituents (g), a group of formula R¹³ --(CH₂)_(m) --CO-- where R¹³and m are as defined above or a group of formula HET--CO-- where Het isas defined above, and

R¹² represents a hydrogen atom, a C₁ -C₅ alkyl group, a C₁ -C₁₀ alkylgroup having at least one substituent selected from the group consistingof substituents (j), a C₁ -C₁₀ alkanoyl group, a C₃ -C₁₀ alkenoyl group,a substituted C₁ -C₁₀ alkanoyl or C₃ -C₁₀ alkenoyl group having at leastone substituent selected from the group consisting of substituents (f),an arylcarbonyl group wherein the aryl part is a C₆ -C₁₀ carbocyclicaryl group which is unsubstituted or has at least one substituentselected from the group consisting of substituents (g), or said group offormula R¹³ --(CH₂)_(m) --CO-- or Het--CO--; and

said substituents (j) are selected from the group consisting of hydroxygroups, C₁ -C₅ alkoxy groups, phenyl groups, phenyl proups having atleast one substituent selected form the group consisting of substituents(g), C₂ -C₁₁ alkanoyloxy groups, C₂ -C₁₁ alkanoyloxy groups substitutedby a group of formula --COOR^(8a) where R^(8a) is as defined above, C₃-C₁₁ alkanoyloxy groups substituted by a group of formula --COOR^(8a)where R^(8a) is as defined above, C₃ -C₁₁ alkenoyloxy groups substitutedby a group of formula --COOR^(8a) where R^(8a) is as defined above,phenylalkenoyloxy groups where the alkenyl part is C₂ -C₁₀ and thephenyl part is unsubstituted or has at least one substituent selectedfrom the group consisting of substituents (g), benzoyloxy groups,benzoyloxy groups having at least one substituent selected from thegroup consisting of substituents (g), groups of formula --COOR^(8a)where R^(8a) is as defined above, benzyloxycarbonyl groups and groups offormula --COR⁹ R¹⁰ where R⁹ and R¹⁰ are as defined above;

U represents

(i) where W represents a group of formula --CH₂ --, >C═O, >CH₂ OR¹¹ or>C═N--OR¹², a group of formula --CH₂ --,

(ii) with W, a group of formula --CH═CH--, or

(iii) where W represents a group of formula >C═O or >C═N--OR¹⁴, in whichR¹⁴ represents any one of the acyl groups defined for R¹², with R¹ andthe carbon atom to which R¹ is attached, a group of formula --CH═C<.

(2) Compounds as defined in (1) above, where:

R¹, R², R⁴, R⁵, Ar, W and U are as defined in (1);

R⁶ and R⁷ both represent hydrogen atoms;

R³ and R¹¹ are independently selected from the group consisting ofhydrogen atoms, C₁ -C₁₀ alkanoyl groups, C₃ -C₁₀ alkenoyl groups, C₁-C₁₀ alkanoyl or C₃ -C₁₀ alkenoyl groups having at least one substituentselected from the group consisting of substituents (f), arylcarbonylgroups as defined in (1) above, and groups of formulae R¹³ --(CH₂)_(m)--CO-- and Het--CO-- where R¹³, m and Het are as defined in (1) above;and

R¹² represents any one of the groups or atoms defined for R³ and R¹¹ ora C₁ -C₅ alkyl groups or a C₁ -C₃ alkyl group having at least onesubstituent selected from the group consisting of substituents (f)defined in (1) above.

(3) Compounds as defined in (1) above, where:

R¹, R², R⁴, R⁵, Ar, W and U are as defined in (1);

R³, R⁶, R⁷ and R¹² are independently selected from the group consistingof hydrogen atoms, C₁ -C₅ alkyl groups, C₁ -C₅ alkyl groups substitutedby a group of formula --COOR^(8a) where R^(8a) is as defined in (1)above, C₂ -C₅ hydroxyalkyl groups, C₁ -C₅ alkyl groups substituted by aC₁ -C₅ alkoxy group, C₂ -C₅ alkyl groups substituted by a group offormula --O--CO--R⁵³ where R⁵³ is as defined in (1) above and C₁ -C₃alkyl groups substituted by a single substituent selected from the groupconsisting of substituents (h) defined in (1) above; and

R¹¹ represents a hydrogen atom, an acetyl group or a benzoyl group; or

R¹² represents a hydrogen atom, a C₁ -C₅ alkyl group, a C₁ -C₁₀ alkylgroup having at least one substituent selected from the group consistingof substituents (k), a C₂ -C₆ alkanoyl group, a C₂ -C₁₀ alkanoyl grouphaving at least one substituent selected from the group consisting ofsubstituents (1), a C₃ -C₅ alkenoyl group, a C₃ -C₅ alkenoyl grouphaving at least one substituent selected from the group consisting ofsubstituents (1), a benzoyl group, a benzoyl group having at least onesubstituent selected from the group consisting of substituents (m), apyridinecarbonyl group, a furoyl group, a thenoyl group or apyridinecarbonyl, furoyl or thenoyl group having at least onesubstituent selected from the group consisting of C₁ -C₅ alkyl groups;

said substituents (k) are selected from the group consisting of hydroxygroups, phenyl groups, phenyl groups having at least one substituentselected from the group consisting of substituents (m), C₂ -C₅alkanoyloxy groups, C₂ -C₁₀ alkanoyloxy or C₃ -C₁₀ alkenoyloxy groupssubstituted by a group of formula --COOR^(8a) where R^(8a) is as definedin (1) above, C₃ -C₁₀ alkenoyloxy groups substituted by a phenyl groupwhere the phenyl group is unsubstituted or has at least one substituentselected from the group consisting of substituents (m), benzoyloxygroups, benzoyloxy groups having at least one substituent selected fromthe group consisting of substituents (m), groups of formula --COOR^(8a)where R^(8a) is as defined in (1) above and substituents (h) as definedin (1) above;

said substituents (1) are selected from the group consisting of phenylgroups, carboxy groups, alkoxycarbonyl groups where the alkoxy part isC₁ -C₅ and benzyloxycarbonyl groups; and

said substituents (m) are selected from the group consisting of C₁ -C₅alkyl groups, C₁ -C₅ alkoxy groups, halogen atoms and trifluoromethylgroups. PG,35

(4) Compounds of formula (I) in which:

R¹ represents an alkyl group selected from the group consisting ofmethyl, ethyl, isobutyl, pentyl, hexyl, 3,3-dimethylbutyl, heptyl,4,4-dimethylpentyl, octyl, 5,5-dimethylhexyl, nonyl and3,7-dimethyloctyl groups;

R² represents a hydrogen atom or a methyl group;

R³ represents a hydrogen atom, a C₁ -C₁₀ alkanoyl group, a C₃ -C₁₀alkenoyl group, a substituted C₁ -C₁₀ alkanoyl or C₃ -C₁₀ alkenoyl grouphaving at least one substituent selected from the group consisting ofsubstituents (f) defined in (1) above, a benzoyl group, a benzoyl grouphaving at least one substituent selected from the group consisting ofsubstituents (n), an aralkanoyl group of formula R¹⁵ --(CH₂)_(m) --CO--

where R¹⁵ represents a phenyl group or a phenyl group having at leastone substituent selected from the group consisting of substituents (n),and m is an integer from 1 to 5,

a pyridinecarbonyl group, a furoyl group, a thenoyl group, a C₁ -C₃alkyl group, a C₁ -C₃ alkyl group substituted by a group of formula--COOR^(8a) where R^(8a) is as defined in (1) above, a C₂ -C₃hydroxyalkyl group, a C₁ -C₅ alkyl group substituted by a C₁ -C₅ alkoxygroup, a C₂ -C₅ alkyl group substituted by a C₂ -C₄ alkanoyloxy or abenzoyloxy group or a methyl group having a single substituent selectedfrom the group consisting of substituents (h);

said substituents (n) are selected from the group consisting of C₁ -C₅alkyl groups, C₁ -C₅ alkoxy groups and halogen atoms;

R⁴ represents a C₁ -C₁₀ alkyl group;

R⁵ represents a hydrogen atom or a C₁ -C₃ alkyl group;

R⁶ and R⁷ are independently selected from the group consisting ofhydrogen atoms, C₁ -C₃ alkyl groups, C₁ -C₃ alkyl groups substituted bya group of formula --COOR^(8a) where R^(8a) is as defined in (1) above,C₂ -C₃ hydroxyalkyl groups, C₁ -C₅ alkyl groups substituted by a C₁ -C₅alkoxy groups, C₂ -C₅ alkyl groups substituted by a C₂ -C₄ alkanoyloxyor a benzoyloxy group, and methyl groups substituted by a singlesubstituent selected from the group consisting of substituents (h);

Ar represents a o-phenylene, m-phenylene or p-phenylene group or apyridine-diyl group which is attached to the part of said compound offormula (I) of formula --(CH₂)_(n) --O-- at its 2-position and isattached to the --CH₂ -thiazolidine group at its 5- or 6-position, saidphenylene and pyridine-diyl groups being unsubstituted or having amethyl substituent;

W represents a group of formula --CH₂ --, >C═O, >CH--OR¹¹ or >C═N--OR¹²,where:

R¹¹ represents a hydrogen atom or any one of the acyl groups definedabove for R³ ; and

R¹² represents a benzyl group, any one of the groups or atoms definedabove for R³, a pyridinecarbonyl group or a pyridinecarbonyl grouphaving at least one substituent selected from the group consisting of C₁-C₅ alkyl groups;

and U represents

(i) where W represents a group of formula --CH₂ --, >C═O, >CH--OR¹¹ or>C═N--OR¹², a group of formula --CH₂ --,

(ii) with W, a group of formula --CH═CH--, or

(iii) where W represents a group of formula >C═O, with R¹ and the carbonatom to which R¹ is attached, a group of formula --CH═C>.

(5) Compounds as defined in (4) above, where:

R¹, R², R⁴, R⁵, Ar, W and U are as defined in (4) above;

R⁶ and R⁷ are both hydrogen atoms;

R³ and R¹¹ are independently selected from the group consisting ofhydrogen atoms, C₁ -C₁₀ alkanoyl groups, C₃ -C₁₀ alkenoyl groups, C₁-C₁₀ alkanoyl or C₃ -C₁₀ alkenoyl groups having at least one substituentselected from the group consisting of substituents (f) defined above,benzoyl groups, benzoyl groups having at least one substituent selectedfrom the group consisting of substituents (n) defined in (4) above,groups of formula R¹⁵ --(CH₂)_(m) --CO-- where R¹⁵ and m are as definedin (4) above, pyridinecarbonyl groups, furoyl groups and thenoyl groups;and

R¹² represents a hydrogen atom, a methyl group, a benzyl group, at-butoxycarbonylmethyl group or any one of the acyl groups defined abovefor R³ and R¹¹.

(6) Compounds as defined in (4) above, where:

R¹, R², R⁴, R⁵, Ar, W and U are as defined in (4) above;

R³, R⁶ and R⁷ are independently selected from the group consisting of C₁-C₃ alkyl groups, C₁ -C₃ alkyl groups substituted by a group of formula--COOR^(8a) where R^(8a) is as defined in (1) above, C₂ -C₃ hydroxyalkylgroups, C₁ -C₅ alkyl groups substituted by a C₁ -C₅ alkoxy group, C₂ -C₅alkyl groups substituted by a C₂ -C₄ alkanoyloxy or a benzoyloxy group,and methyl groups having a single substituent selected from the groupconsisting of substituents (h) defined in (1) above;

R¹¹ represents a hydrogen atom;

R¹² represents a hydrogen atom, a C₁ -C₃ alkyl group having at least onesubstituent selected from the group consisting of substituents (o), a C₂-C₄ alkanoyl group, a C₂ -C₄ alkanoyl group substituted by a group offormula --COOR^(8a) where R^(8a) is as defined in (1) above, an acryloylgroup, acryloyl group having a β-substituent selected from the groupconsisting of substituents (f) defined above, a benzoyl group, a benzoylgroup having at least one substituent selected from the group consistingof substituents (q), a pyridinecarbonyl group, a pyridinecarbonyl grouphaving at least one substituent selected from the group consisting of C₁-C₅ alkyl groups or any one of the groups defined above for R³, R⁶ andR⁷ ;

said substituents (o) are selected from the group consisting of carboxygroups and alkoxycarbonyl groups where the alkoxy part is C₁ -C₅ ; and

said substituents (q) are selected from the group consisting of methylgroups, ethyl groups, methoxy groups and ethoxy groups.

(7) Compounds of formula (I) in which:

R¹ represents an alkyl group selected from the group consisting ofmethyl, isobutyl, hexyl, heptyl, octyl, nonyl and 3,7-dimethyloctylgroups;

R² represents a hydrogen atom or a methyl group;

R³ represents a hydrogen atom, a C₁ -C₅ alkanoyl group, C₃ -C₅ alkenoylgroup, a cinnamoyl group, a group of formula R¹⁶ OOC(CH₂)_(m) CO--

where R¹⁶ represents a hydrogen atom or a C₁ -C₅ alkyl group and m is aninteger from 1 to 5,

a cis- or trans- group of formula R¹⁷ OOC.CH═CH--CO--

where R¹⁷ represents a hydrogen atom, a C₁ -C₅ alkyl group or a benzylgroup,

2-, 3- or 4-pyridinecarbonyl group or a C₁ -C₃ alkyl group substitutedby a group of formula --COOR^(8a) where R^(8a) is as defined in (1)above;

R⁴ represents an alkyl group selected from the group consisting ofmethyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl,1,1,3,3-tetramethylbutyl, 1,1-dimethylbutyl and 1,1-dimethylpropylgroups;

R⁵ represents a hydrogen atom or a methyl group;

R⁶ and R⁷ are independently selected from the group consisting ofhydrogen atoms and C₁ -C₃ alkyl groups substituted by a group of formula--COOR^(8a) where R^(8a) is as defined in (1) above;

Ar represents a p-phenylene group, a m-phenylene group having a methylgroup at the position ortho to the position of attachment to the groupof formula --(CH₂)_(n) --O-- or a pyridine-diyl group attached to saidgroup of formula --(CH₂)_(n) --O-- at the 2-position and to the --CH₂-thiazolidine group at the 5-position;

W represents a group of formula --CH₂ --, >C═O, >C═N--OH, >C═N--OCH₂COOH or >C═N--OCOR¹⁸

where R¹⁸ represents a C₁ -C₅ alkyl group; and

U represents a group of formula --CH₂ --.

(7-a) Compounds of formula (I) in which:

R¹ represents an alkyl group selected from the group consisting ofhexyl, heptyl, octyl, nonyl and 3,7-dimethyloctyl groups;

R² represents a hydrogen atom or a methyl group;

R³ represents a hydrogen atom, a C₁ -C_(C) ₅ alkanoyl group, C₃ -C₅alkenoyl group, a cinnamoyl group, a group of formula R¹⁶ OOC(CH₂)_(m)CO--

where R¹⁶ represents a hydrogen atom or a C₁ -C₅ alkyl group and m is aninteger from 1 to 5,

a cis- or trans- group of formula R¹⁷ OOC.CH═CH--CO--

where R¹⁷ represents a hydrogen atom, C₁ -C₅ alkyl group or a benzylgroup,

2-, 3- or 4-pyridinecarbonyl group or a C₁ -C₃ alkyl group substitutedby a group of formula --COOR^(8a) where R^(8a) is as defined in (1)above;

R⁴ represents an alkyl group selected from the group consisting ofmethyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl,1,1,3,3-tetramethylbutyl, 1,1-dimethylbutyl and 1,1-dimethylpropylgroups;

R⁵ represents a hydrogen atom or a methyl group;

R⁶ and R⁷ are independently selected from the group consisting ofhydrogen atoms and C₁ -C₃ alkyl groups substituted by a group of formula--COOR^(8a) where R^(8a) is as defined in (1) above;

Ar represents a p-phenylene group, a m-phenylene group having a methylgroup at the position ortho to the position of attachment to the groupof formula --(CH₂)_(n) --O-- or a pyridine-diyl group attached to saidgroup of formula --(CH₂)_(n) --O-- at the 2-position and to the --CH₂-thiazolidine group at the 5-position;

W represents a group of formula --CH₂ --, >C═O or >C═N--OR¹²

where R¹² is as defined in (9) below or represents a C₁ -C₅ alkyl groupor a C₁ -C₅ alkyl group substituted by a phenyl group where the phenylgroup is unsubstituted or has at least one substituent selected from thegroup consisting of substituents (n) as defined in (4) above; and

U represents a group of formula --CH₂ --.

(7-b) Compounds of formula (I) in which:

R¹ represents an alkyl group selected from the group consisting ofmethyl, isobutyl, hexyl, heptyl, octyl, nonyl and 3,7-dimethyloctylgroups;

R² represents a hydrogen atom or a methyl group;

R³ represents a hydrogen atom, a C₁ -C₅ alkanoyl group, C₃ -C₅ alkenoylgroup, a cinnamoyl group, a group of formula R¹⁶ OOC(CH₂)_(m) CO--

where R¹⁶ represents a hydrogen atom or a C₁ -C₅ alkyl group and m is aninteger from 1 to 5,

a cis- or trans- group of formula R¹⁷ OOC.CH═CH--CO--

where R¹⁷ represents a hydrogen atom, a C₁ -C₅ alkyl group or a benzylgroup,

a 2-, 3- or 4-pyridinecarbonyl group or a C₁ -C₃ alkyl group substitutedby a group of formula --COOR^(8a) where R^(8a) is as defined in (1)above;

R⁴ represents an alkyl group selected from the group consisting ofhexyl, heptyl, octyl, 1,1,3,3-tetramethylbutyl, 1,1-dimethylbutyl and1,1-dimethylpropyl groups;

R⁵ represents a hydrogen atom or a methyl group;

R⁶ and R⁷ are independently selected from the group consisting ofhydrogen atoms and C₁ -C₃ alkyl groups substituted by a group of formula--COOR^(8a) where R^(8a) is as defined in (1) above;

Ar represents a p-phenylene group, a m-phenylene group having a methylgroup at the position ortho to the position of attachment to the groupof formula --(CH₂)_(n) --O-- or a pyridine-diyl group attached to saidgroup of formula --(CH₂)_(n) --O-- at the 2-position and to the --CH₂-thiazolidine group at the 5-position;

W represents a group of formula --CH₂ --, >C═O or >C═N--OR¹²

where R¹² is as defined in (9) below or represents a C₁ -C₅ alkyl groupor a C₁ -C₅ alkyl group substituted by a phenyl group where the phenylgroup is unsubstituted or has at least one substituent selected from thegroup consisting of substituents (n) as defined in (4) above; and

U represents a group of formula --CH₂ --.

(7-c) Compounds of formula (I) in which:

R¹ represents an alkyl group selected from the group consisting ofmethyl, isobutyl, hexyl, heptyl, octyl, nonyl and 3,7-dimethyloctylgroups;

R² represents a hydrogen atom or a methyl group;

R³ represents C₁ -C₃ alkyl group substituted by a group of formula--COOR^(8a)

where R^(8a) is as defined in (1) above;

R⁴ represents an alkyl group selected from the group consisting ofmethyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl,1,1,3,3-tetramethylbutyl, 1,1-dimethylbutyl and 1,1-dimethylpropylgroups;

R⁵ represents a hydrogen atom or a methyl group;

R⁶ and R⁷ are both hydrogen atoms;

Ar represents a p-phenylene group, a m-phenylene group having a methylgroup at the position ortho to the position of attachment to the groupof formula --(CH₂)_(n) --O-- or a pyridine-diyl group attached to saidgroup of formula --(CH₂)_(n) --O-- at the 2-position and to the --CH₂-thiazolidine group at the 5-position;

W represents a group of formula --CH₂ --, >C═O, >C═N--OH, or>C═N--O--(C₁ -C₃ alkyl)--COOR^(8a) where R^(8a) is as defined in (1)above;

U represents a group of formula --CH₂ --; and

n is 1 or 2.

(7-d) Compounds of formula (I) in which:

R¹ represents an alkyl group selected from the group consisting ofmethyl, isobutyl, hexyl, heptyl, octyl, nonyl and 3,7-dimethyloctylgroups;

R² represents a hydrogen atom or a methyl group;

R³ represents --CH₂ --COO(C₁ -C₅ alkyl) group;

R⁴ represents an alkyl group selected from the group consisting ofmethyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl,1,1,3,3-tetramethylbutyl, 1,1-dimethylbutyl and 1,1-dimethylpropylgroups;

R⁵ represents a hydrogen atom or a methyl group;

R⁶ and R⁷ are both hydrogen atoms;

Ar represents a p-phenylene group, a m-phenylene group having a methylgroup at the position ortho to the position of attachment to the groupof formula --(CH₂)_(n) --O-- or a pyridine-diyl group attached to saidgroup of formula --(CH₂)_(n) --O-- at the 2-position and to the --CH₂-thiazolidine group at the 5-position;

W represents a group of formula --CH₂ --, >C═O, >C═N--OH, or>C═N--O--(C₁ -C₃ alkyl)--COO(C₁ -C₅ alkyl);

U represents a group of formula --CH₂ --; and

n is 2 or 2.

(8) Compounds as defined in (7) above, where:

R¹, R², R⁴, R⁵, Ar and U are as defined in (7) above;

R³ represents a hydrogen atom, a C₁ -C₅ alkanoyl group, a C₃ -C₅alkenoyl group, a cinnamoyl group, a group of formula R¹⁶ OOC(CH₂)_(m)CO-- where R¹⁶ and m are as defined in (7) above, a cis or trans- groupof formula R¹⁷ OOC.CH═CH--CO-- where R¹⁷ is as defined in (7) above, ora 2-, 3- or 4-pyridinecarbonyl group;

R⁶ and R⁷ are both hydrogen atoms;

W represents a group of formula >C═NOR¹² where R¹² is as defined in (9)below; and

n is 1 or 2.

(9) Compounds as defined in (7) above, where:

R¹, R², R⁴, R⁵, Ar and U are as defined in (7) above;

R³, R⁶ and R⁷ are independently selected from the group consisting of C₁-C₃ alkyl groups substituted by a group of formula --COOR^(8a) whereR^(8a) is as defined in (1) above;

W represents a group of formula >CH₂, >C═O or >C═NOR¹² ;

R¹² represents a hydrogen atom, a group of formula --(CH₂)₃ COOR^(8a),--CH₂ COOR^(8a), --C(CH₃)₂ COOR^(8a), --COCH₂ CH₂ COOR^(8a) or--CO--CH═CH--COOR^(8a) where R^(8a) is as defined in (1) above, anacetyl group, a cinnamoyl group, a benzoyl group, a pyridinecarbonylgroup or any one of the groups defined above for R³, R⁶ and R⁷ ; and

n is 1 or 2.

(9-a) Compounds as defined in (7) above, where:

R¹, R², R⁴, R⁵, Ar and U are as defined in (7) above;

R³ represents a hydrogen atom, a C₁ -C₁₀ alkanoyl group, a C₃ -C₁₀alkenoyl group, a C₁ -C₁₀ alkanoyl or C₃ -C₁₀ alkenoyl group having atleast one substituent selected from the group consisting of substituents(f), an arylcarbonyl group as defined in (1) above, a group of formulaR¹³ --(CH₂)_(m) --CO-- or Het--CO-- where R¹³, m and Het are as definedin (1) above or a C₁ -C₃ alkyl group substituted by a group of formula--COOR^(8a) where R^(8a) is as defined in (1) above;

R⁶ represents a C₁ -C₃ alkyl group substituted by a group of formula--COOR^(8a) where R^(8a) is as defined in (1) above;

R⁷ represents a hydrogen atom or a C₁ -C₃ alkyl group substituted by agroup of formula --COOR^(8a) where R^(8a) is as defined in (1) above;

W represents a group of formula >CH₂, >C═O or >C═NOR¹², where

R¹² represents a hydrogen atom, a group of formula --(CH₂)₃ COOR^(8a),--CH₂ COOR^(8a), --C(CH₃)₂ COOR^(8a), --COCH₂ CH₂ COOR^(8a) or--CO--CH═CH --COOR^(8a) where R^(8a) is as defined in (1) above, anacetyl group, a cinnamoyl group, a benzoyl group, a pyridinecarbonylgroup or a C₁ -C₃ alkyl group substituted by a group of formula--COOR^(8a) where R^(8a) is as defined in (1) above; and

n is 1 or 2.

Specific examples of compounds of the invention are given in thefollowing Tables 1-26, referring to the formula (I-1) to (I-26). In theTables, the following abbreviations are used:

    ______________________________________                                        Ac               acetyl                                                       Boz              benzoyl                                                      Bu               butyl                                                         .sub.- iBu      isobutyl                                                      .sub.- tBu      t-butyl                                                      Bz               benzyl                                                       Dc               decyl                                                        3,3-DMB          3,3-dimethylbutyl                                            5,5-DMH          5,5-dimethylhexyl                                            3,7-DMO          3,7-dimethyloctyl                                            7,7-DMO          7,7-dimethyloctyl                                            Et               ethyl                                                        Hp               heptyl                                                       Hx               hexyl                                                        Hxd              hexadecyl                                                    Ic               icosyl                                                       Me               methyl                                                       Mor              morpholino                                                   Nn               nonyl                                                        Oc               octyl                                                        Ocd              octadecyl                                                    Ph               phenyl                                                       Phn              phenylene                                                    Pip              piperidino                                                   Piz              piperazinyl                                                  Pn               pentyl                                                        .sub.- iPn      isopentyl                                                     -nPn            neopentyl                                                    Pr               propyl                                                        .sub.- iPr      isopropyl                                                    Pydi             pyridine-diyl                                                Pyl              pyrrolidinyl                                                 Pyr              pyridyl                                                      TMB              1,1,3,3-tetramethylbutyl                                     Trd              tridecyl                                                     ______________________________________                                    

In the case of the divalent group represented by Ar, where appropriate,the number given first is the position of attachment of that group tothe group represented by --(CH₂)_(n) --O-- in the compound of formula(I), whilst the number given second is the position of attachment ofthat group to the --CH₂ -thiazolidine group.

Compounds of formula (I-1): ##STR3## are as defined in Table 1:

                                      TABLE 1                                     __________________________________________________________________________    Cpd. No.                                                                           R.sup.3       W           Ar                                             __________________________________________________________________________     1   H                                                                                            ##STR4##   6-Me-1,3-Phn                                    2   Ac                                                                                           ##STR5##   6-Me-1,3-Phn                                    3   H                                                                                            ##STR6##   6-Me-1,3-Phn                                    4   H                                                                                            ##STR7##   6-Me-1,3-Phn                                    5   H                                                                                            ##STR8##   2,5-Pydi                                        6   H                                                                                            ##STR9##   2,5-Pydi                                        7   Ac                                                                                           ##STR10##  2,5-Pydi                                        8   H                                                                                            ##STR11##  2,5-Pydi                                        9   H                                                                                            ##STR12##  p-Phn                                          10   H                                                                                            ##STR13##  p-Phn                                          11   Ac                                                                                           ##STR14##  p-Phn                                          12   Boz                                                                                          ##STR15##  p-Phn                                          13   3-PyrCO                                                                                      ##STR16##  p-Phn                                          14   H                                                                                            ##STR17##  p-Phn                                          15   H                                                                                            ##STR18##  p-Phn                                          16   H                                                                                            ##STR19##  p-Phn                                          17   H                                                                                            ##STR20##  p-Phn                                          18   Ac                                                                                           ##STR21##  p-Phn                                          19   H                                                                                            ##STR22##  p-Phn                                          20   H                                                                                            ##STR23##  p-Phn                                          21   H                                                                                            ##STR24##  p-Phn                                          22   Me(CH.sub.2).sub.14 CO                                                                       ##STR25##  p-Phn                                          23   HOOC(CH.sub.2).sub.2 CO                                                                      ##STR26##  p-Phn                                          24   HOOCCHCHCO-(cis)                                                                             ##STR27##  p-Phn                                          25   HOOC(CH.sub.2).sub.2 CO                                                                      ##STR28##  p-Phn                                          26   HOOC(CH.sub.2).sub.3 CO                                                                      ##STR29##  p-Phn                                          27   HOOC(CH.sub.2).sub.2 CO                                                                      ##STR30##  p-Phn                                          28   HOOC(CH.sub.2).sub.2 CO                                                                      ##STR31##  2,5-Pydi                                       29   HOOC(CH.sub.2).sub.2 CO                                                                      ##STR32##  p-Phn                                          30   HOOC(CH.sub.2).sub.2 CO                                                                      ##STR33##  2,5-Pydi                                       __________________________________________________________________________

Compounds of formula (I-2): ##STR34## are as defined in Table 2:

                  TABLE 2                                                         ______________________________________                                        Cpd.                                                                          No.  R.sup.3       W                Ar                                        ______________________________________                                        31   H                                                                                            ##STR35##       6-Me-1,3- Phn                             32   H                                                                                            ##STR36##       6-Me-1,3- Phn                             33   H                                                                                            ##STR37##       6-Me-1,3- Phn                             34   H                                                                                            ##STR38##       2,5-Pydi                                  35   Ac                                                                                           ##STR39##       2,5-Pydi                                  36   H                                                                                            ##STR40##       2,5-Pydi                                  37   Ac                                                                                           ##STR41##       2,5-Pydi                                  38   H                                                                                            ##STR42##       2,5-Pydi                                  39   H                                                                                            ##STR43##       p-Phn                                     40   Ac                                                                                           ##STR44##       p-Phn                                     41   Boz                                                                                          ##STR45##       p-Phn                                     42   3-PyrCO                                                                                      ##STR46##       p-Phn                                     43   H                                                                                            ##STR47##       p-Phn                                     44   H                                                                                            ##STR48##       p-Phn                                     45   H                                                                                            ##STR49##       p-Phn                                     46   H                                                                                            ##STR50##       p-Phn                                     47   H                                                                                            ##STR51##       p-Phn                                     48   H                                                                                            ##STR52##       p-Phn                                     49   H                                                                                            ##STR53##       p-Phn                                     50   HOOC(CH.sub.2).sub.6 CO                                                                      ##STR54##       m-Phn                                     ______________________________________                                         ##STR55##

                                      TABLE 3                                     __________________________________________________________________________    Cpd. No.                                                                           R.sup.1                                                                            R.sup.3      -n                                                                              W      Ar                                            __________________________________________________________________________    51   me   H           1                                                                                       p-Phn                                         52   Me   H           1                                                                                 ##STR56##                                                                           p-Phn                                         53   Me   H           1                                                                                 ##STR57##                                                                           p-Phn                                         54   Me   H           2                                                                                 ##STR58##                                                                           p-Phn                                         55   Me   H           1                                                                                 ##STR59##                                                                           6-Me-1,3-Phn                                  56   Me   Ac          1                                                                                 ##STR60##                                                                           p-Phn                                         57   Me   Ac          1                                                                                 ##STR61##                                                                           p-Phn                                         58   Me   H           1                                                                                 ##STR62##                                                                           6-Me-1,3-Phn                                  59   Me   H           2                                                                                 ##STR63##                                                                           6-Me-1,3-Phn                                  60   Me   H           1                                                                                 ##STR64##                                                                           2,5-Pydi                                      61   Me   H           1                                                                                 ##STR65##                                                                           2,5-Pydi                                      62   Me   H           1                                                                                 ##STR66##                                                                           2,5-Pydi                                      63    .sub.-iPr                                                                         H           1                                                                                 ##STR67##                                                                           p-Phn                                         64   Bz   H           1                                                                                 ##STR68##                                                                           p-Phn                                         65   Bz   H           1                                                                                 ##STR69##                                                                           p-Phn                                         66   Bz   H           1                                                                                 ##STR70##                                                                           2,5-Pydi                                      67   Hx   H           1                                                                                 ##STR71##                                                                           p-Phn                                         68   Hx   H           1                                                                                 ##STR72##                                                                           p-Phn                                         69   Hx   H           1                                                                                 ##STR73##                                                                           p-Phn                                         70   Hx   H           1                                                                                 ##STR74##                                                                           2,5-Pydi                                      71   3,3-DMB                                                                            H           1                                                                                 ##STR75##                                                                           p-Phn                                         72   Hp   H           1                                                                                 ##STR76##                                                                           p-Phn                                         73   Oc   H           1                                                                                 ##STR77##                                                                           p-Phn                                         74   Oc   H           1                                                                                 ##STR78##                                                                           p-Phn                                         75   Oc   H           1                                                                                 ##STR79##                                                                           p-Phn                                         76   Oc   H           1                                                                                 ##STR80##                                                                           2,5-Pydi                                      77   5,5-DMH                                                                            H           1                                                                                 ##STR81##                                                                           p-Phn                                         78   5,5-DMH                                                                            H           1                                                                                 ##STR82##                                                                           p-Phn                                         79   5,5-DMH                                                                            H           1                                                                                 ##STR83##                                                                           p-Phn                                         80   Dc   H           1                                                                                 ##STR84##                                                                           p-Phn                                         81   Me   HOOCCHCHCO  1                                                                                 ##STR85##                                                                           p-Phn                                                   (trans)                                                             __________________________________________________________________________

Compounds of formula (I-4): ##STR86## are as defined in Table 4:

                  TABLE 4                                                         ______________________________________                                        Cpd. No.                                                                              R.sup.1   R.sup.2                                                                              R.sup.4                                                                             R.sup.5                                                                             W                                        ______________________________________                                        82      Me         .sub.-iPr                                                                            .sub.-iPr                                                                          Me                                                                                   ##STR87##                               83      Et        Me     Me    Me                                                                                   ##STR88##                               84      Et        H       .sub.-tBu                                                                          H                                                                                    ##STR89##                               85      Pr        Me     Me    Me                                                                                   ##STR90##                               86       .sub.-iBu                                                                              Me     Me    Me                                                                                   ##STR91##                               87      Bz        Me     Me    Me                                                                                   ##STR92##                               88      1-MeHx    H       .sub.-tBu                                                                          H                                                                                    ##STR93##                               89      Oc        Me     Me    Me                                                                                   ##STR94##                               90      Oc        Me     Me    Me                                                                                   ##STR95##                               91      Oc        Me     Me    Me                                                                                   ##STR96##                               92      Oc        H       .sub.-tBu                                                                          H                                                                                    ##STR97##                               93      5,5-DMH   Me     Me    Me                                                                                   ##STR98##                               94      Dc        Me     Me    Me                                                                                   ##STR99##                               ______________________________________                                    

Compounds of formula (I-5): ##STR100## are as defined in Table 5:

                  TABLE 5                                                         ______________________________________                                        Cpd.                                                                          No.     R.sup.1   R.sup.2 R.sup.4                                                                             R.sup.5                                                                             W                                       ______________________________________                                         95     Et         .sub.-iPr                                                                             .sub.-iPr                                                                          H                                                                                    ##STR101##                              96     Bz        Me      Me    Me                                                                                   ##STR102##                              97     Bz        Me      Me    Me                                                                                   ##STR103##                              98     2-OMeBz   H        .sub.-tBu                                                                          H                                                                                    ##STR104##                              99     Hx        Me      Me    Me                                                                                   ##STR105##                             100     Hx        Me      Me    Me                                                                                   ##STR106##                             101     Hx        Me      Me    Me                                                                                   ##STR107##                             102     Hx        H        .sub.-tBu                                                                          H                                                                                    ##STR108##                             103     Hx        H        .sub.-tBu                                                                          H                                                                                    ##STR109##                             104     Hx        H        .sub. -tBu                                                                         H                                                                                    ##STR110##                             105     3,3-DMB   H        .sub.-tBu                                                                          H                                                                                    ##STR111##                             106     Hp        Me      Me    Me                                                                                   ##STR112##                             107     Hp        H        .sub.-tBu                                                                          H                                                                                    ##STR113##                             108     Oc        Me      Me    Me                                                                                   ##STR114##                             109     Oc        Me      Me    Me                                                                                   ##STR115##                             110     Oc        Me      Me    Me                                                                                   ##STR116##                             111     5,5-DMH   Me      Me    Me                                                                                   ##STR117##                             112     5,5-DMH   Me      Me    Me                                                                                   ##STR118##                             113     5,5-DMH   H        .sub.-tBu                                                                          H                                                                                    ##STR119##                             114     Dc        Me      Me    Me                                                                                   ##STR120##                             ______________________________________                                         ##STR121##

                  TABLE 6                                                         ______________________________________                                        Cpd.                                                                          No.  R.sup.1    R.sup.2 R.sup.4                                                                             R.sup.5                                                                             W        n                                ______________________________________                                        115   .sub.-iPr H        .sub.-tBu                                                                          H                                                                                            1                                116  Bz         Me      Me    Me                                                                                   ##STR122##                                                                            1                                117  Bz         Me      Me    Me                                                                                   ##STR123##                                                                            1                                118   .sub.-iBu Me      Me    Me                                                                                   ##STR124##                                                                            1                                119  Bz         H        .sub.-tBu                                                                          H                                                                                    ##STR125##                                                                            1                                120  4-MeBz     H       Me    H                                                                                    ##STR126##                                                                            1                                121  3-ClBz      .sub.-iPr                                                                             .sub.-iPr                                                                          H                                                                                    ##STR127##                                                                            1                                122  2-PhEt     Me      Me    Me                                                                                   ##STR128##                                                                            2                                123  Hx         Me      Me    Me                                                                                   ##STR129##                                                                            1                                124  Hx         Me      Me    Me                                                                                   ##STR130##                                                                            1                                125  Hx         Me      Me    Me                                                                                   ##STR131##                                                                            1                                126  Hx         H        .sub.-tBu                                                                          H                                                                                    ##STR132##                                                                            1                                127  Hx         H        .sub.-tBu                                                                          H                                                                                    ##STR133##                                                                            1                                128  Hx         H        .sub.-tBu                                                                          H                                                                                    ##STR134##                                                                            1                                129  1-MePn     Me      Me    Me                                                                                   ##STR135##                                                                            1                                130  3,3-DMB    Me      Me    Me                                                                                   ##STR136##                                                                            1                                131  3,3-DMB    Me      Me    Me                                                                                   ##STR137##                                                                            1                                132  3,3-DMB    Me      Me    Me                                                                                   ##STR138##                                                                            1                                133  3,3-DMB    H        .sub.-tBu                                                                          H                                                                                    ##STR139##                                                                            1                                134  1-EtBu     Me      Me    Me                                                                                   ##STR140##                                                                            2                                135  3-MePn      .sub.-iPr                                                                             .sub.-iPr                                                                          H                                                                                    ##STR141##                                                                            1                                136  Hp         Me      Me    Me                                                                                   ##STR142##                                                                            1                                137  Hp         Me      Me    Me                                                                                   ##STR143##                                                                            1                                138  Hp         Me      Me    Me                                                                                   ##STR144##                                                                            1                                139  Hp         H        .sub.-tBu                                                                          H                                                                                    ##STR145##                                                                            1                                140  Hp         H        .sub.-tBu                                                                          H                                                                                    ##STR146##                                                                            1                                141  4,4-diMePn Me      Me    Me                                                                                   ##STR147##                                                                            1                                142  Oc         Me      Me    Me                                                                                   ##STR148##                                                                            1                                143  Oc         Me      Me    Me                                                                                   ##STR149##                                                                            1                                144  Oc         Me      Me    Me                                                                                   ##STR150##                                                                            1                                145  Oc         H        .sub.-tBu                                                                          H                                                                                    ##STR151##                                                                            1                                146  Oc         H        .sub.-tBu                                                                          H                                                                                    ##STR152##                                                                            1                                147  Oc         H        .sub.-tBu                                                                          H                                                                                    ##STR153##                                                                            1                                148  5,5-DMH    Me      Me    Me                                                                                   ##STR154##                                                                            1                                149  5,5-DMH    Me      Me    Me                                                                                   ##STR155##                                                                            1                                150  5,5-DMH    Me      Me    Me                                                                                   ##STR156##                                                                            1                                151  5,5-DMH    H        .sub.-tBu                                                                          H                                                                                    ##STR157##                                                                            1                                152  5,5-DMH    H        .sub.-tBu                                                                          H                                                                                    ##STR158##                                                                            1                                153  5,5-DMH    H        .sub.-tBu                                                                          H                                                                                    ##STR159##                                                                            1                                154  Nn         Me      Me    Me                                                                                   ##STR160##                                                                            1                                155  Dc         Me      Me    Me                                                                                   ##STR161##                                                                            1                                156  Dc         H        .sub.-tBu                                                                          H                                                                                    ##STR162##                                                                            1                                157  1-MeNn     Me      Me    H                                                                                    ##STR163##                                                                            1                                158  3,7-DMO    Me      Me    Me                                                                                   ##STR164##                                                                            1                                159  3,7-DMO    Me      Me    Me                                                                                   ##STR165##                                                                            1                                160  3,7-DMO    Me      Me    Me                                                                                   ##STR166##                                                                            1                                161  3,7-DMO    H        .sub.-tBu                                                                          H                                                                                    ##STR167##                                                                            1                                162  3,7-DMO    H        .sub.-tBu                                                                          H                                                                                    ##STR168##                                                                            1                                163  7,7-DMO    Me      Me    Me                                                                                   ##STR169##                                                                            1                                164  7,7-DMO    Me      Me    Me                                                                                   ##STR170##                                                                            1                                ______________________________________                                         ##STR171##

                                      TABLE 7                                     __________________________________________________________________________    Cpd.                                                                          No.                                                                              R.sup.1 R.sup.2                                                                          R.sup.3    R.sup.5                                                                          W     Ar     n                                    __________________________________________________________________________    165                                                                              2-(3-OEtPh)Et                                                                         H  H          H                                                                                      2-Me-1,4-Phn                                                                         1                                    166                                                                              Hx      Me H          H                                                                                 ##STR172##                                                                         3-Me-1,4-Phn                                                                         1                                    167                                                                              Oc      Me Ac         Me                                                                                ##STR173##                                                                         p-Phn  1                                    168                                                                              Oc      Me Ac         Me                                                                                ##STR174##                                                                         p-Phn  1                                    169                                                                              5,5-DMH Me Ac         Me                                                                                ##STR175##                                                                         2,5-Pydi                                                                             1                                    170                                                                              3,7-DMO Me Ac         Me                                                                                ##STR176##                                                                         p-Phn  1                                    171                                                                              7,7-DMO Me Ac         Me                                                                                ##STR177##                                                                         p-Phn  1                                    172                                                                              Pr      Me EtOOC(CH.sub.2).sub.2 CO                                                                 Me                                                                                ##STR178##                                                                         p-Phn  1                                    173                                                                              Oc      Me HOOC(CH.sub.2).sub.4 CO                                                                  Me                                                                                ##STR179##                                                                         p-Phn  2                                    __________________________________________________________________________     ##STR180##

                                      TABLE 8                                     __________________________________________________________________________    Cpd.                                                                          No.                                                                              R.sup.3        W'       Ar       -n                                        __________________________________________________________________________    174                                                                              H              O        p-Phn   1                                          175                                                                              Ac             O        p-Phn   1                                          176                                                                              H              O        p-Phn   2                                          177                                                                              Ac             O        p-Phn   2                                          178                                                                              H              O        p-Phn   3                                          179                                                                              Ac             O        p-Phn   3                                          180                                                                              Boz            O        p-Phn   1                                          181                                                                              H              NOH      p-Phn   1                                          182                                                                              Ac             NOAc     p-Phn   1                                          183                                                                              H              NOH      p-Phn   2                                          184                                                                              H              NOH      p-Phn   3                                          185                                                                              H              O        6-Me-1,3-Phn                                                                          1                                          186                                                                              Ac             O        6-Me-1,3-Phn                                                                          1                                          187                                                                              H              O        6-Me-1,3-Phn                                                                          2                                          188                                                                              H              NOH      6-Me-1,3-Phn                                                                          1                                          189                                                                              Ac             NOAc     6-Me-1,3-Phn                                                                          1                                          190                                                                              H              O        2,5-Pydi                                                                              1                                          191                                                                              Ac             O        2,5-Pydi                                                                              1                                          192                                                                              H              O        2,5-Pydi                                                                              2                                          193                                                                              H              NOH      2,5-Pydi                                                                              1                                          194                                                                              HOOC(CH.sub.2).sub.2 CO--                                                                    O        p-Phn   1                                          195                                                                              HOOCCH═CHCO-(cis)                                                                        O        p-Phn   1                                          196                                                                              HOOCCH═CHCO-(trans)                                                                      O        2,5-Pydi                                                                              1                                          197                                                                              HOOC(CH.sub.2).sub.2 CO--                                                                    O        p-Phn   2                                          198                                                                              HOOC(CH.sub.2).sub.2 CO--                                                                    NOH      p-Phn   1                                          199                                                                              HOOC(CH.sub.2).sub.2 CO--                                                                    NOCH.sub.2 COOH                                                                        p-Phn   1                                          200                                                                              HOOC(CH.sub.2).sub.2 CO--                                                                    NOCH.sub.2 COOH                                                                        2,5-Pydi                                                                              1                                          201                                                                              HOOC(CH.sub.2 ).sub.2 CO--                                                                   NOCH.sub.2 COO .sub.- tBu                                                              p-Phn   1                                          202                                                                              EtOOC(CH.sub.2).sub.6 CO--                                                                   NOCH.sub.2 COOEt                                                                       p-Phn   1                                          __________________________________________________________________________     ##STR181##

                  TABLE 9                                                         ______________________________________                                        Cpd.                                                                          No.   R.sup.3        W'       Ar         -n                                   ______________________________________                                        203   H              O        p-Phn     1                                     204   Ac             O        p-Phn     1                                     205   H              O        p-Phn     2                                     206   Ac             O        p-Phn     2                                     207   H              NOH      p-Phn     1                                     208   H              O        6-Me-1,3-Phn                                                                            1                                     209   Ac             O        6-Me-1,3-Phn                                                                            1                                     210   H              O        2,5-Pydi  1                                     211   Ac             O        2,5-Pydi  1                                     212   Ac             NOH      2,5-Pydi  1                                     213   HOOC(CH.sub.2).sub.2 CO--                                                                    O        p-Phn     1                                     ______________________________________                                    

Compounds of formula (I-10): ##STR182## are as defined in Table 10:

                  TABLE 10                                                        ______________________________________                                        Cpd.                                                                          No.  R.sup.3       W'           Ar        -n                                  ______________________________________                                        214  H             O            p-Phn    1                                    215  Ac            O            p-Phn    1                                    216  Ac            NOH          p-Phn    1                                    217  H             NOH          p-Phn    2                                    218  H             O            6-Me-1,3-Phn                                                                           1                                    219  Ac            O            6-Me-1,3-Phn                                                                           1                                    220  H             O            6-Me-1,3-Phn                                                                           2                                    221  H             NOH          6-Me-1,3-Phn                                                                           1                                    222  H             O            2,5-Pydi 1                                    223  HOOC(CH.sub.2).sub.2 CO--                                                                   O            p-Phn    1                                    224  HOOC(CH.sub.2).sub.2 CO--                                                                   NOCH.sub.2 COOH                                                                            2,5-Pydi 1                                    ______________________________________                                    

Compounds of formula (I-11): ##STR183## are as defined in Table 11:

                  TABLE 11                                                        ______________________________________                                        Cpd.                                                                          No.   R.sup.2 R.sup.3        R.sup.4                                                                             Ar                                         ______________________________________                                        225    .sub.- iPr                                                                           H               .sub.- iPr                                                                         p-Phn                                      226   Me      EtOOC(CH.sub.2).sub.4 CO--                                                                   Me    6-Me-1,3-Phn                               ______________________________________                                    

Compounds of formula (I-12): ##STR184## are as defined in Table 12:##STR185##

                                      TABLE 12                                    __________________________________________________________________________    Cpd.                                                                          No.                                                                              R.sup.1                                                                            R.sup.2                                                                           R.sup.3   R.sup.4                                                                           R.sup.5                                                                           Ar                                              __________________________________________________________________________    227                                                                              Me   Me  H         Me  Me  p-Phn                                           228                                                                              Me   Me  Ac        Me  Me  p-Phn                                           229                                                                              Me   Me  Boz       Me  Me  p-Phn                                           230                                                                              Me   Me  H         Me  Me  6-Me-1,3-Phn                                    231                                                                              Me   Me  Ac        Me  Me  6-Me-1,3-Phn                                    232                                                                              Me   Me  H         Me  Me  2,5-Pydi                                        233                                                                              Me   Me  Ac        Me  Me  2,5-Pydi                                        234                                                                              Me   H   H          .sub.- tBu                                                                       H   p-Phn                                           235                                                                              Me   H   Ac         .sub.- tBu                                                                       H   p-Phn                                           236                                                                              Me   H   H          .sub.- tBu                                                                       H   6-Me-1,3-Phn                                    237                                                                              Me   H   Ac         .sub.- tBu                                                                       H   6-Me-1,3-Phn                                    238                                                                              Me   H   H          .sub.- tBu                                                                       H   2,5-Pydi                                        239                                                                              Me   H   Ac         .sub.- tBu                                                                       H   2,5-Pydi                                        240                                                                              Me    .sub.- iPr                                                                       H          .sub.- iPr                                                                       H   p-Phn                                           241                                                                              Me   H   H         TMB H   p-Phn                                           242                                                                              Me   H   H         TMB H   6-Me-1,3-Phn                                    243                                                                              Me   H   H         TMB H   2,5-Pydi                                        244                                                                              Et   Me  H         Me  Me  p-Phn                                           245                                                                              Pr   H   H          .sub.- tBu                                                                       H   p-Phn                                           246                                                                              Pr   H   Ac         .sub.- tBu                                                                       H   p-Phn                                           247                                                                               .sub.- iPr                                                                        H   H         TMB H   p-Phn                                           248                                                                               .sub.- iBu                                                                        Me  H         Me  Me  p-Phn                                           249                                                                               .sub.- iBu                                                                        Me  Ac        Me  Me  p-Phn                                           250                                                                              Bu   H   H          .sub.- tBu                                                                       H   p-Phn                                           251                                                                               .sub.- iBu                                                                        H   H         TMB H   p-Phn                                           252                                                                               -nPn                                                                              Me  H         Me  Me  p-Phn                                           253                                                                               .sub.- iPn                                                                        H   H          .sub.- tBu                                                                       H   p-Phn                                           254                                                                              Pn   H   H         TMB H   2,5-Pydi                                        255                                                                              Hx   Me  H         Me  Me  p-Phn                                           256                                                                              Oc   Me  H         Me  Me  p-Phn                                           257                                                                              Dc   Me  H         Me  Me  p-Phn                                           258                                                                              3,7-DMO                                                                            H   H          .sub.- tBu                                                                       H   p-Phn                                           259                                                                              7,7-DMO                                                                            H   H          .sub.- tBu                                                                       H   6-Me-1,3-Phn                                    260                                                                              3,7-DMO                                                                            H   H          .sub.- tBu                                                                       H   2,5-Pydi                                        261                                                                              7,7-DMO                                                                            H   H         TMB H   p-Phn                                           262                                                                              Bz   H   H         TMB H   p-Phn                                           263                                                                              Me   Me  HOOC(CH.sub.2).sub.2 CO--                                                               Me  Me  p-Phn                                           264                                                                              Me   H   HOOC(CH.sub.2).sub.2 CO--                                                                .sub.- tBu                                                                       H   p-Phn                                           265                                                                              Me   H   HOOC(CH.sub.2).sub.2 CO--                                                               TMB H   p-Phn                                           __________________________________________________________________________

Compounds of formula (I-13): ##STR186## are as defined in Table 13:

                  TABLE 13                                                        ______________________________________                                        Cpd.                                                                          No.       R.sup.3     W                                                       ______________________________________                                        266       Et                                                                                         ##STR187##                                             267        .sub.-iPr                                                                                 ##STR188##                                             268       Me                                                                                         ##STR189##                                             269       Pn                                                                                         ##STR190##                                             270       2-HOEt                                                                                     ##STR191##                                             271       2-HOEt                                                                                     ##STR192##                                             272       5-AcOPn                                                                                    ##STR193##                                             273       2-HOEt                                                                                     ##STR194##                                             ______________________________________                                         ##STR195##

                                      TABLE 14                                    __________________________________________________________________________    Cpd.                                                                          No.                                                                              R.sup.1                                                                            R.sup.2                                                                          R.sup.4                                                                           R.sup.5                                                                          R.sup.103                                                                        W            Ar   n r                                    __________________________________________________________________________    274                                                                              Me   Me Me  Me H                                                                                             p-Phn                                                                              1 1                                    275                                                                              Me   Me Me  Me Me                                                                                ##STR196##  p-Phn                                                                              1 1                                    276                                                                              Me   Me Me  Me Et                                                                                ##STR197##  p-Phn                                                                              1 1                                    277                                                                              Me   Me Me  Me  .sub.-tBu                                                                        ##STR198##  p-Phn                                                                              1 1                                    278                                                                              Me   Me Me  Me H                                                                                 ##STR199##  p-Phn                                                                              1 1                                    279                                                                              Me   Me Me  Me Me                                                                                ##STR200##  p-Phn                                                                              1 1                                    280                                                                              Me   Me Me  Me Et                                                                                ##STR201##  p-Phn                                                                              1 1                                    281                                                                              Me   Me Me  Me  .sub.- iPr                                                                       ##STR202##  p-Phn                                                                              1 1                                    282                                                                              Me   Me Me  Me  .sub.-tBu                                                                        ##STR203##  p-Phn                                                                              1 1                                    283                                                                              Me   Me Me  Me H                                                                                 ##STR204##  p-Phn                                                                              1 1                                    284                                                                              Me   Me Me  Me H                                                                                 ##STR205##  p-Phn                                                                              1 1                                    285                                                                              Me   Me Me  Me Et                                                                                ##STR206##  p-Phn                                                                              1 1                                    286                                                                              Me   Me Me  Me  .sub.-tBu                                                                        ##STR207##  p-Phn                                                                              1 1                                    287                                                                              Me   Me Me  Me H                                                                                 ##STR208##  p-Phn                                                                              1 1                                    288                                                                              Me   Me Me  Me Et                                                                                ##STR209##  p-Phn                                                                              1 1                                    289                                                                              Me   Me Me  Me  .sub.-tBu                                                                        ##STR210##  p-Phn                                                                              1 1                                    290                                                                              Me   Me Me  Me H                                                                                 ##STR211##  p-Phn                                                                              1 1                                    291                                                                              Me   Me Me  Me H                                                                                 ##STR212##  p-Phn                                                                              2 1                                    292                                                                              Me   Me Me  Me H                                                                                 ##STR213##  p-Phn                                                                              1 2                                    293                                                                              Me   Me Me  Me H                                                                                 ##STR214##  m-Phn                                                                              1 1                                    294                                                                              Me   Me Me  Me H                                                                                 ##STR215##  2,5-Pydi                                                                           1 1                                    295                                                                              Me   Me Me  Me H                                                                                 ##STR216##  2,5-Pydi                                                                           1 2                                    296                                                                              Me   Me Me  Me H                                                                                 ##STR217##  p-Phn                                                                              2 2                                    297                                                                              Me   Me Me  Me H                                                                                 ##STR218##  2,5-Pydi                                                                           1 1                                    298                                                                              Me   Me Me  Me H                                                                                 ##STR219##  2,5-Pydi                                                                           3 3                                    299                                                                              Me   Me Me  Me H                                                                                 ##STR220##  p-Phn                                                                              1 1                                    300                                                                              Me   Me Me  Me H                                                                                 ##STR221##  p-Phn                                                                              1 1                                    301                                                                              Me   H   .sub.- tBu                                                                       H  H                                                                                 ##STR222##  p-Phn                                                                              1 1                                    302                                                                              Me   H   .sub.-tBu                                                                        H  Et                                                                                ##STR223##  p-Phn                                                                              1 1                                    303                                                                              Me   H   .sub.-tBu                                                                        H  t-Bu                                                                              ##STR224##  p-Phn                                                                              1 1                                    304                                                                              Me   H   .sub.-tBu                                                                        H  H                                                                                 ##STR225##  p-Phn                                                                              1 1                                    305                                                                              Me   H   .sub.-tBu                                                                        H  H                                                                                 ##STR226##  p-Phn                                                                              1 1                                    306                                                                              Me   H   .sub.-tBu                                                                        H  Et                                                                                ##STR227##  p-Phn                                                                              1 1                                    307                                                                              Me   H   .sub.-tBu                                                                        H  H                                                                                 ##STR228##  p-Phn                                                                              1 1                                    308                                                                              Me   H   .sub.-tBu                                                                        H  H                                                                                 ##STR229##  p-Phn                                                                              1 1                                    309                                                                              Me   H   .sub.-tBu                                                                        H  H                                                                                 ##STR230##  2,5-Pydi                                                                           1 1                                    310                                                                              Me   H   .sub.-tBu                                                                        H  H                                                                                 ##STR231##  2,5-Pydi                                                                           1 1                                    311                                                                              Me   H   .sub.-tBu                                                                        H  H                                                                                 ##STR232##  2,5-Pydi                                                                           1 1                                    312                                                                              Et    .sub.-iPr                                                                        .sub.-iPr                                                                        H  Me                                                                                ##STR233##  p-Phn                                                                              1 1                                    313                                                                              Pr   H  Me  H  H                                                                                 ##STR234##  p-Phn                                                                              1 1                                    314                                                                               .sub.-iPr                                                                         H   .sub.-tBu                                                                        H  H                                                                                 ##STR235##  m-Phn                                                                              1 1                                    315                                                                               .sub.-iBu                                                                         Me Me  Me H                                                                                 ##STR236##  p-Phn                                                                              1 1                                    316                                                                               .sub.-iBu                                                                         Me Me  Me H                                                                                 ##STR237##  p-Phn                                                                              1 1                                    317                                                                              Oc   Me Me  Me H                                                                                 ##STR238##  p-Phn                                                                              1 1                                    318                                                                              Oc   Me Me  Me H                                                                                 ##STR239##  2,5-Pydi                                                                           2 1                                    319                                                                              Me   Me MeO MeO                                                                              H                                                                                 ##STR240##  p-Phn                                                                              1 1                                    320                                                                              Me   Me MeO MeO                                                                              H                                                                                 ##STR241##  p-Phn                                                                              1 1                                    321                                                                              Me   H  TMB H  H                                                                                 ##STR242##  p-Phn                                                                              1 1                                    322                                                                              Me   H  TMB H  H                                                                                 ##STR243##  p-Phn                                                                              1 1                                    323                                                                              Me   H  TMB H  H                                                                                 ##STR244##  p-Phn                                                                              1 1                                    324                                                                              Me   H  TMB H  H                                                                                 ##STR245##  p-Phn                                                                              1 1                                    325                                                                              Bu   H  TMB H  H                                                                                 ##STR246##  2,5-Pydi                                                                           1 3                                    326                                                                              5,5-DMH                                                                            Me Me  Me H                                                                                 ##STR247##  p-Phn                                                                              1 1                                    327                                                                              Me   Me Me  Me Et                                                                                ##STR248##  p-Phn                                                                              1 5                                    328                                                                              Me   Me Me  Me H                                                                                 ##STR249##  p-Phn                                                                              1 1                                    __________________________________________________________________________

                                      TABLE 15                                    __________________________________________________________________________    Cpd.                                                                          No.                                                                              R.sup.1                                                                            R.sup.2                                                                          R.sup.3        R.sup.4                                                                           R.sup.5                                                                          W            Ar     n                        __________________________________________________________________________    329                                                                              Me   H  HO(CH.sub.2).sub.2 OCOCH.sub.2                                                               TMB H                                                                                 ##STR250##  p-Phn  1                        330                                                                              Pr   H  HO(CH.sub.2).sub.2 OCOCH.sub.2                                                                .sub.-tBu                                                                        H                                                                                 ##STR251##  p-Phn  1                        331                                                                              Et   H  HO(CH.sub.2).sub.3 OCOCH.sub.2                                                               Me  H                                                                                 ##STR252##  p-Phn  1                        332                                                                              Me   Me HO(CH.sub.2).sub.5 OCOCH.sub.2                                                               Me  Me                                                                                ##STR253##  p-Phn  1                        333                                                                              Me   Me MeO(CH.sub.2).sub.2 OCOCH.sub.2                                                              Me  Me                                                                                ##STR254##  p-Phn  1                        334                                                                              Me   Me MeO(CH.sub.2).sub.2 OCOCH.sub.2                                                              Me  Me                                                                                ##STR255##  p-Phn  1                        335                                                                              Me   Me MeO(CH.sub.2).sub.2 OCOCH.sub.2                                                              Me  Me                                                                                ##STR256##  p-Phn  1                        336                                                                              Me   Me MeO(CH.sub.2).sub.2 OCOCH.sub.2                                                              Me  Me                                                                                ##STR257##  p-Phn  1                        337                                                                              Me   H  MeO(CH.sub.2).sub.2 OCOCH.sub.2                                                               .sub.-tBu                                                                        H                                                                                 ##STR258##  p-Phn  1                        338                                                                              Me   H  MeO(CH.sub.2).sub.2 OCOCH.sub.2                                                               .sub.-tBu                                                                        H                                                                                 ##STR259##  p-Phn  1                        339                                                                              Me   H  MeO(CH.sub.2).sub.2 OCOCH.sub.2                                                              TMB H                                                                                 ##STR260##  p-Phn  1                        340                                                                              Me   H  MeO(CH.sub.2).sub.2 OCOCH.sub.2                                                              TMB H                                                                                 ##STR261##  p-Phn  1                        341                                                                              Me   Me MeO(CH.sub.2).sub.2 OCOCH.sub.2                                                              Me  Me                                                                                ##STR262##  p-Phn  1                        342                                                                              Me   Me MeO(CH.sub.2).sub.2 OCOCH.sub.2                                                              Me  Me                                                                                ##STR263##  6-Me-1,3-Phn                                                                         1                        343                                                                              3,3-DMB                                                                            Me EtO(CH.sub.2 ).sub.2 OCOCH.sub.2                                                             Me  Me                                                                                ##STR264##  p-Phn  1                        344                                                                              Me   H   .sub.-iPrO(CH.sub.2).sub.3 OCOCH.sub.2                                                      Me  H                                                                                 ##STR265##  p-Phn  1                        345                                                                              5,5-DMH                                                                            H  MeO(CH.sub.2).sub.5 OCOCH.sub.2                                                               .sub.-iPr                                                                        H                                                                                 ##STR266##  p-Phn  1                        346                                                                              Me   Me AcO(CH.sub.2).sub.2 OCOCH.sub.2                                                              Me  Me                                                                                ##STR267##  2,5-Pydi                                                                             2                        347                                                                              Bz   Me BozO(CH.sub.2).sub.2 OCOCH.sub.2                                                             Me  Me                                                                                ##STR268##  p-Phn  1                        348                                                                              Me   Me MeO(CH.sub.2).sub.2 OCO(CH.sub.2).sub.2                                                      MeO MeO                                                                               ##STR269##  p-Phn  1                        349                                                                              7,7-DMO                                                                            Me MeO(CH.sub.2).sub.2 OCO(CH.sub.2).sub.3                                                      Me  Me                                                                                ##STR270##  6-Me-1,3-Phn                                                                         1                        350                                                                              Me   Me MeO(CH.sub.2).sub.2 OCO(CH.sub.2).sub.5                                                      Me  Me                                                                                ##STR271##  p-Phn  3                        351                                                                              Me   Me MeOOCCH(Me)    Me  Me                                                                                ##STR272##  p-Phn  1                        352                                                                              Me   Me MeOOCCH(Me)CH.sub.2                                                                          Me  Me                                                                                ##STR273##  p-Phn  1                        353                                                                              Me   Me MeOOCCMe.sub.2 Me  Me                                                                                ##STR274##  p-Phn  1                        354                                                                              Me   Me EtOOCCMe.sub.2 Me  Me                                                                                ##STR275##  p-Phn  1                        355                                                                              Me   Me EtOOCCMe.sub.2 Me  Me                                                                                ##STR276##  p-Phn  1                        356                                                                              Me   Me EtOOCCMe.sub.2 Me  Me                                                                                ##STR277##  p-Phn  1                        357                                                                              Me   Me EtOOCCMe.sub.2 Me  Me                                                                                ##STR278##  p-Phn  1                        358                                                                              Me   Me EtOOCCMe.sub.2 Me  Me                                                                                ##STR279##  p-Phn  1                        359                                                                              Me   H  EtOOCCMe.sub.2  .sub.-tBu                                                                        H                                                                                 ##STR280##  p-Phn  1                        360                                                                              Me   H  EtOOCCMe.sub.2  .sub. -tBu                                                                       H                                                                                 ##STR281##  p-Phn  1                        361                                                                              Me   H  EtOOCCMe.sub.2  .sub.-tBu                                                                        H                                                                                 ##STR282##  p-Phn  1                        362                                                                              Me   H  EtOOCCMe.sub.2  .sub.-tBu                                                                        H                                                                                 ##STR283##  p-Phn  1                        363                                                                              Me   H  EtOOCCMe.sub.2  .sub.-tBu                                                                        H                                                                                 ##STR284##  p-Phn  1                        364                                                                              Me   Me EtOOCCMe.sub.2 Me  Me                                                                                ##STR285##  p-Phn  1                        365                                                                              Me   Me HOOCCMe.sub.2  Me  Me                                                                                ##STR286##  p-Phn  1                        366                                                                              Me   Me HOOCCMe.sub.2  Me  Me                                                                                ##STR287##  p-Phn  1                        367                                                                              Me   Me HOOCCMe.sub.2  Me  Me                                                                                ##STR288##  p-Phn  1                        368                                                                              Me   Me HOOCCMe.sub.2  Me  Me                                                                                ##STR289##  p-Phn  1                        369                                                                              Me   Me HOOCCMe.sub.2  Me  Me                                                                                ##STR290##  p-Phn  1                        370                                                                              Me   Me HOOCCMe.sub.2  Me  Me                                                                                ##STR291##  p-Phn  1                        371                                                                              Me   H  HOOCCMe.sub.2   .sub.-tBu                                                                        H                                                                                 ##STR292##  p-Phn  1                        372                                                                              Me   H  HOOCCMe.sub.2   .sub.-tBu                                                                        H                                                                                 ##STR293##  p-Phn  1                        373                                                                              Me   H  HOOCCMe.sub.2   .sub.-tBu                                                                        H                                                                                 ##STR294##  p-Phn  1                        374                                                                              Me   H  HOOCCMe.sub.2  TMB H                                                                                 ##STR295##  p-Phn  1                        375                                                                              Me   H  HOOCCMe.sub.2  TMB H                                                                                 ##STR296##  p-Phn  1                        376                                                                              Me   Me H.sub.2 NCOCH.sub.2                                                                          Me  Me                                                                                ##STR297##  p-Phn  1                        377                                                                              Me   Me MeNHCOCH.sub.2 Me  Me                                                                                ##STR298##  p-Phn  1                        378                                                                              Me   H  Me.sub.2 NCOCH.sub.2                                                                          .sub.-tBu                                                                        H                                                                                 ##STR299##  p-Phn  1                        379                                                                              Me   Me Et(Me)NCOCH.sub.2                                                                            Me  Me                                                                                ##STR300##  p-Phn  1                        380                                                                              Me   Me MorCOCH.sub.2  Me  Me                                                                                ##STR301##  p-Phn  1                        381                                                                              Me   Me 1-PipCOCH.sub.2                                                                              Me  Me                                                                                ##STR302##  p-Phn  1                        382                                                                              Me   Me 1-PylCOCH.sub.2                                                                              Me  Me                                                                                ##STR303##  6-Me-1,3-Phn                                                                         1                        383                                                                              Me   H  1-PizCOCH.sub.2                                                                              TMB H                                                                                 ##STR304##  p-Phn  1                        384                                                                              Me   Me 4-Me-1-PizCOCH.sub.2                                                                         Me  Me                                                                                ##STR305##  p-Phn  1                        385                                                                              Me   Me Me.sub.2 NCOCH.sub.2 CH.sub.2                                                                Me  Me                                                                                ##STR306##  p-Phn  2                        386                                                                              Me   Me Me.sub.2 NCOCMe.sub.2                                                                        Me  Me                                                                                ##STR307##  p-Phn  1                        387                                                                              Me   Me Me.sub.2 NCO(CH.sub.2).sub.5                                                                 Me  Me                                                                                ##STR308##  p-Phn  1                        __________________________________________________________________________

                                      TABLE 16                                    __________________________________________________________________________    Cpd.                                                                          No.                                                                              R.sup.1                                                                            R.sup.2                                                                          R.sup.3      R.sup.4                                                                           R.sup.5                                                                          R.sup.6                                                                            W           Ar     n                      __________________________________________________________________________    388                                                                              Me   Me HOOCCH.sub.2 Me  Me Oc                                                                                  ##STR309## p-Phn  1                      389                                                                              Me   H  EtOOCCH.sub.2                                                                              Me  H  5,5-DMH                                                                             ##STR310## p-Phn  3                      390                                                                              Me   Me MeOCH.sub.2 CH.sub.2 OCOCH.sub.2                                                           Me  Me Me                                                                                  ##STR311## p-Phn  1                      391                                                                              Me   Me AcOCH.sub.2 CH.sub.2 OCOCH.sub.2                                                           MeO MeO                                                                              2-MeOEt                                                                             ##STR312## 2,5-Pydi                                                                             2                      392                                                                              Me   Me HOOCCMe.sub.2                                                                              Me  Me Bu                                                                                  ##STR313## 5-Me-1,3-Phn                                                                         1                      393                                                                              Me   H  HOOCCH.sub.2 CH.sub.2                                                                      TMB H  3,3-DMB                                                                             ##STR314## p-Phn  1                      394                                                                              Me   Me H.sub.2 NCOCH.sub.2                                                                        Me  Me Dc                                                                                  ##STR315## p-Phn  1                      395                                                                              7,7-DMO                                                                            H  Et(Me)NCOCH.sub.2                                                                           .sub.-tBu                                                                        H   .sub.-iBu                                                                          ##STR316## p-Phn  1                      396                                                                              Me   Me H            Me  Me Et                                                                                  ##STR317## p-Phn  1                      397                                                                              3,3-DMB                                                                            H  Me           TMB H  Pr                                                                                  ##STR318## p-Phn  1                      398                                                                              Me   Me Ac           Me  Me  .sub.-iPr                                                                          ##STR319## p-Phn  1                      399                                                                              Me   H  Me            .sub.-tBu                                                                        H  Bu                                                                                  ##STR320## p-Phn  1                      400                                                                              Me   Me H            Me  Me 2-OHEt                                                                              ##STR321## p-Phn  1                      __________________________________________________________________________

                                      TABLE 17                                    __________________________________________________________________________    Cpd                                                                           No.                                                                              R.sup.1                                                                          R.sup.2                                                                          R.sup.4                                                                           R.sup.5                                                                          R.sup.106                                                                        W            Ar   n p                                      __________________________________________________________________________    401                                                                              Me Me Me  Me H                                                                                 ##STR322##  p-Phn                                                                              1 1                                      402                                                                              Me Me Me  Me Me                                                                                ##STR323##  p-Phn                                                                              1 1                                      403                                                                              Me Me Me  Me Et                                                                                ##STR324##  p-Phn                                                                              1 1                                      404                                                                              Me Me Me  Me  .sub.-tBu                                                                        ##STR325##  p-Phn                                                                              1 1                                      405                                                                              Me Me Me  Me H                                                                                 ##STR326##  p-Phn                                                                              1 1                                      406                                                                              Me Me Me  Me Me                                                                                ##STR327##  p-Phn                                                                              1 1                                      407                                                                              Me Me Me  Me  .sub.-iPr                                                                        ##STR328##  p-Phn                                                                              1 1                                      408                                                                              Me Me Me  Me  .sub.-tBu                                                                        ##STR329##  p-Phn                                                                              1 1                                      409                                                                              Me Me Me  Me H                                                                                 ##STR330##  p-Phn                                                                              1 1                                      410                                                                              Me Me Me  Me H                                                                                 ##STR331##  p-Phn                                                                              1 1                                      411                                                                              Me Me Me  Me  .sub.-tBu                                                                        ##STR332##  p-Phn                                                                              1 1                                      412                                                                              Me Me Me  Me H                                                                                 ##STR333##  p-Phn                                                                              1 1                                      413                                                                              Me Me Me  Me H                                                                                 ##STR334##  p-Phn                                                                              1 1                                      414                                                                              Me Me Me  Me  .sub.-tBu                                                                        ##STR335##  p-Phn                                                                              1 1                                      415                                                                              Me Me Me  Me H                                                                                 ##STR336##  p-Phn                                                                              2 1                                      416                                                                              Me Me Me  Me H                                                                                 ##STR337##  p-Phn                                                                              1 2                                      417                                                                              Me Me Me  Me H                                                                                 ##STR338##  m-Phn                                                                              1 1                                      418                                                                              Me Me Me  Me H                                                                                 ##STR339##  2,5-Pydi                                                                           1 1                                      419                                                                              Me Me Me  Me H                                                                                 ##STR340##  2,5-Pydi                                                                           1 2                                      420                                                                              Me Me Me  Me H                                                                                 ##STR341##  p-Phn                                                                              2 2                                      421                                                                              Me Me Me  Me H                                                                                 ##STR342##  2,5-Pydi                                                                           1 1                                      422                                                                              Me Me Me  Me H                                                                                 ##STR343##  2,5-Pydi                                                                           3 3                                      423                                                                              Me Me Me  Me H                                                                                 ##STR344##  p-Phn                                                                              1 1                                      424                                                                              Me Me Me  Me H                                                                                 ##STR345##  p-Phn                                                                              1 1                                      425                                                                              Me H   .sub.-tBu                                                                        H  H                                                                                 ##STR346##  p-Phn                                                                              1 1                                      426                                                                              Me H   .sub.-tBu                                                                        H   .sub.-tBu                                                                        ##STR347##  p-Phn                                                                              1 1                                      427                                                                              Me H   .sub.-tBu                                                                        H  H                                                                                 ##STR348##  p-Phn                                                                              1 1                                      428                                                                              Me H   .sub.-tBu                                                                        H  H                                                                                 ##STR349##  p-Phn                                                                              1 1                                      429                                                                              Me H   .sub.-tBu                                                                        H  H                                                                                 ##STR350##  p-Phn                                                                              1 1                                      430                                                                              Me H   .sub.-tBu                                                                        H  H                                                                                 ##STR351##  2,5-Pydi                                                                           1 1                                      431                                                                              Me H   .sub.-tBu                                                                        H  H                                                                                 ##STR352##  2,5-Pydi                                                                           1 1                                      432                                                                              Me H   .sub.-tBu                                                                        H  H                                                                                 ##STR353##  2,5-Pydi                                                                           1 1                                      433                                                                              Et  .sub.-iPr                                                                        .sub.-iPr                                                                        H  Me                                                                                ##STR354##  p-Phn                                                                              1 1                                      434                                                                              Pr H  Me  H  H                                                                                 ##STR355##  p-Phn                                                                              1 1                                      435                                                                               .sub.-iPr                                                                       H   .sub.-tBu                                                                        H  H                                                                                 ##STR356##  m-Phn                                                                              1 1                                      436                                                                               .sub.-iBu                                                                       Me Me  Me H                                                                                 ##STR357##  p-Phn                                                                              1 1                                      437                                                                               .sub.-iBu                                                                       Me Me  Me H                                                                                 ##STR358##  p-Phn                                                                              1 1                                      438                                                                              Oc Me Me  Me H                                                                                 ##STR359##  p-Phn                                                                              1 1                                      439                                                                              Oc Me Me  Me H                                                                                 ##STR360##  2,5-Pydi                                                                           2 1                                      440                                                                              Me Me MeO MeO                                                                              H                                                                                 ##STR361##  p-Phn                                                                              1 1                                      441                                                                              Me Me MeO MeO                                                                              H                                                                                 ##STR362##  p-Phn                                                                              1 1                                      442                                                                              Me H  TMB H  H                                                                                 ##STR363##  p-Phn                                                                              1 1                                      443                                                                              Me H  TMB H  H                                                                                 ##STR364##  p-Phn                                                                              1 1                                      444                                                                              Me H  TMB H  H                                                                                 ##STR365##  p-Phn                                                                              1 1                                      445                                                                              Me H  TMB H  H                                                                                 ##STR366##  p-Phn                                                                              1 1                                      446                                                                              Bu H  TMB H  H                                                                                 ##STR367##  2,5-Pydi                                                                           1 3                                      __________________________________________________________________________     ##STR368##

                  TABLE 18                                                        ______________________________________                                        Cpd                                                                           No.  R.sup.2                                                                              R.sup.3     R.sup.4                                                                            R.sup.5                                                                            W                                           ______________________________________                                        447  Me     Me          Me   Me                                               448  Me     Ac          Me   Me                                                                                  ##STR369##                                 449  Me     MeOCH.sub.2 Me   Me                                                                                  ##STR370##                                 450  H      Boz          .sub.-tBu                                                                         H                                                                                   ##STR371##                                 451  Me     EtOOCCH.sub.2                                                                             Me   Me                                                                                  ##STR372##                                 ______________________________________                                         ##STR373##

                                      TABLE 19                                    __________________________________________________________________________    Cpd                                                                           No.                                                                              R.sup.2                                                                          R.sup.3 R.sup.4                                                                          R.sup.5                                                                          R.sup.6     W                                             __________________________________________________________________________    452                                                                              Me Ac      Me Me CH.sub.2 COOH                                             453                                                                              Me Ac      Me Me CH.sub.2 COOMe                                                                             ##STR374##                                   454                                                                              Me Ac      Me Me CH.sub.2 COOt-Bu                                                                           ##STR375##                                   455                                                                              Me H       Me Me CMe.sub.2 COOH                                                                             ##STR376##                                   456                                                                              H  Ac       .sub.-tBu                                                                       H  CMe.sub.2 COOH                                                                             ##STR377##                                   457                                                                              Me H       Me Me CMe.sub.2 COOEt                                                                            ##STR378##                                   458                                                                              Me H       Me Me CH.sub.2 CONMe.sub.2                                                                       ##STR379##                                   459                                                                              Me H       Me Me CH.sub.2 C)(4-Me-1-Piz)                                                                    ##STR380##                                   460                                                                              Me HOOCCMe.sub.2                                                                         Me Me CH.sub.2 COOH                                                                              ##STR381##                                   __________________________________________________________________________

Compounds of formulae (I-20), (I-21), (I-22), (I-23) and (I-24):##STR382##

                                      TABLE 20                                    __________________________________________________________________________    Cpd                                                                           No.                                                                              R.sup.1                                                                          R.sup.2                                                                          R.sup.4                                                                           R.sup.5                                                                          R.sup.103                                                                        R.sup.106                                                                        W            Ar   n r p                                 __________________________________________________________________________    461                                                                              Me Me Me  Me H  H                                                                                             p-Phn                                                                              1 1 1                                 462                                                                              Me Me Me  Me Et Et                                                                                ##STR383##  p-Phn                                                                              1 1 1                                 463                                                                              Me Me Me  Me  .sub.-tBu                                                                        .sub.-tBu                                                                        ##STR384##  p-Phn                                                                              1 1 1                                 464                                                                              Me Me Me  Me H  H                                                                                 ##STR385##  p-Phn                                                                              1 1 1                                 465                                                                              Me Me Me  Me Me Me                                                                                ##STR386##  p-Phn                                                                              1 1 1                                 466                                                                              Me Me Me  Me  .sub.-tBu                                                                        .sub.-tBu                                                                        ##STR387##  p-Phn                                                                              1 1 1                                 467                                                                              Me Me Me  Me H  H                                                                                 ##STR388##  p-Phn                                                                              1 1 1                                 468                                                                              Me Me Me  Me  .sub.-tBu                                                                        .sub.-tBu                                                                        ##STR389##  p-Phn                                                                              1 1 1                                 469                                                                              Me Me Me  Me H  H                                                                                 ##STR390##  p-Phn                                                                              1 1 1                                 470                                                                              Me Me Me  Me H  H                                                                                 ##STR391##  p-Phn                                                                              1 1 1                                 471                                                                              Me Me Me  Me  .sub.-tBu                                                                        .sub.-tBu                                                                        ##STR392##  p-Phn                                                                              1 1 1                                 472                                                                              Me Me Me  Me H  H                                                                                 ##STR393##  p-Phn                                                                              1 2 2                                 473                                                                              Me Me Me  Me H  H                                                                                 ##STR394##  p-Phn                                                                              2 1 1                                 474                                                                              Me Me Me  Me H  H                                                                                 ##STR395##  p-Phn                                                                              1 2 1                                 475                                                                              Me Me Me  Me H  H                                                                                 ##STR396##  p-Phn                                                                              2 1 2                                 476                                                                              Me Me Me  Me H  H                                                                                 ##STR397##  m-Phn                                                                              1 3 3                                 477                                                                              Me Me Me  Me H  H                                                                                 ##STR398##  2,5-Pydi                                                                           1 1 1                                 478                                                                              Me Me Me  Me H  H                                                                                 ##STR399##  2,5-Pydi                                                                           1 1 1                                 479                                                                              Me Me Me  Me H  H                                                                                 ##STR400##  2,5-Pydi                                                                           1 1 1                                 480                                                                              Me Me Me  Me H  H                                                                                 ##STR401##  2,5-Pydi                                                                           1 1 1                                 481                                                                              Me Me Me  Me Et  .sub.-iPr                                                                        ##STR402##  2,5-Pydi                                                                           1 1 1                                 482                                                                              Me Me Me  Me H  H                                                                                 ##STR403##  2,5-Pydi                                                                           3 2 2                                 483                                                                              Me Me Me  Me H  H                                                                                 ##STR404##  2,5-Pydi                                                                           1 2 2                                 484                                                                              Me H   .sub.-tBu                                                                        H  H  H                                                                                 ##STR405##  p-Phn                                                                              1 1 1                                 485                                                                              Me H   .sub.-tBu                                                                        H  Et Et                                                                                ##STR406##  p-Phn                                                                              1 1 1                                 486                                                                              Me H   .sub.-tBu                                                                        H   .sub.-tBu                                                                        .sub.-tBu                                                                        ##STR407##  p-Phn                                                                              1 1 1                                 487                                                                              Me H   .sub.-tBu                                                                        H  H  H                                                                                 ##STR408##  p-Phn                                                                              1 1 1                                 488                                                                              Me H   .sub.-tBu                                                                        H   .sub.-tBu                                                                        .sub.-tBu                                                                        ##STR409##  p-Phn                                                                              1 1 1                                 489                                                                              Me H   .sub.-tBu                                                                        H  H  H                                                                                 ##STR410##  p-Phn                                                                              1 1 1                                 490                                                                              Me H   .sub.-tBu                                                                        H  H  H                                                                                 ##STR411##  p-Phn                                                                              1 1 1                                 491                                                                              Me H   .sub.-tBu                                                                        H   .sub. -tBu                                                                       .sub.-tBu                                                                        ##STR412##  p-Phn                                                                              1 1 1                                 492                                                                              Me H   .sub.-tBu                                                                        H  H  H                                                                                 ##STR413##  2,5-Pydi                                                                           1 1 1                                 493                                                                              Et Me Me  Me H  H                                                                                 ##STR414##  p-Phn                                                                              1 2 2                                 494                                                                              Pr Me Me  Me H  H                                                                                 ##STR415##  m-Phn                                                                              2 1 1                                 495                                                                               .sub.-iPr                                                                       H  Me  H  H  H                                                                                 ##STR416##  p-Phn                                                                              2 3 3                                 496                                                                               .sub.-iBu                                                                       Me Me  Me H  H                                                                                 ##STR417##  2,5-Pydi                                                                           1 1 1                                 497                                                                              Oc Me Me  Me H  H                                                                                 ##STR418##  p-Phn                                                                              1 1 1                                 498                                                                              Me Me MeO MeO                                                                              H  H                                                                                 ##STR419##  p-Phn                                                                              1 1 1                                 499                                                                              Me Me MeO MeO                                                                              H  H                                                                                 ##STR420##  p-Phn                                                                              1 1 1                                 500                                                                              Me H  TMB H  H  H                                                                                 ##STR421##  p-Phn                                                                              1 1 1                                 501                                                                              Me H  TMB H  H  H                                                                                 ##STR422##  p-Phn                                                                              1 1 1                                 502                                                                              Me H  TMB H  H  H                                                                                 ##STR423##  p-Phn                                                                              1 1 1                                 503                                                                              Me H  TMB H  H  H                                                                                 ##STR424##  p-Phn                                                                              1 1 1                                 504                                                                              Me H  TMB H  H  H                                                                                 ##STR425##  2,5-Pydi                                                                           1 1 1                                 __________________________________________________________________________

                                      TABLE 21                                    __________________________________________________________________________    Cpd                                                                           No.                                                                              R.sup.2                                                                          R.sup.4                                                                          R.sup.5                                                                          R.sup.103                                                                        R.sup.106                                                                        R.sup.107                                                                        W           Ar   r p q                                   __________________________________________________________________________    505                                                                              Me Me Me H  H  H                                                                                 ##STR426## p-Phn                                                                              1 1 1                                   506                                                                              Me Me Me Et Et Et                                                                                ##STR427## p-Phn                                                                              1 1 1                                   507                                                                              Me Me Me  .sub.-tBu                                                                        .sub.-tBu                                                                        .sub.-tBu                                                                        ##STR428## p-Phn                                                                              1 1 1                                   508                                                                              Me Me Me H  H  H                                                                                 ##STR429## p-Phn                                                                              1 1 1                                   509                                                                              Me Me Me  .sub.-tBu                                                                        .sub.-tBu                                                                        .sub.-tBu                                                                        ##STR430## p-Phn                                                                              1 1 1                                   510                                                                              Me Me Me H  H  H                                                                                 ##STR431## p-Phn                                                                              1 1 1                                   511                                                                              Me Me Me  .sub.-tBu                                                                        .sub.-tBu                                                                        .sub.-tBu                                                                        ##STR432## p-Phn                                                                              1 1 1                                   512                                                                              Me Me Me H  H  H                                                                                 ##STR433## p-Phn                                                                              1 1 1                                   513                                                                              Me Me Me Et Et Et                                                                                ##STR434## p-Phn                                                                              1 1 1                                   514                                                                              Me Me Me H  H  H                                                                                 ##STR435## p-Phn                                                                              2 3 4                                   515                                                                              Me Me Me H  H  H                                                                                 ##STR436## 2,5-Pydi                                                                           1 1 1                                   516                                                                              Me Me Me H  H  H                                                                                 ##STR437## 2,5-Pydi                                                                           1 1 1                                   517                                                                              Me Me Me Et Et Et                                                                                ##STR438## 2,5-Pydi                                                                           1 1 1                                   518                                                                              H  t-Bu                                                                             H  H  H  H                                                                                 ##STR439## p-Phn                                                                              1 1 1                                   519                                                                              H  t-Bu                                                                             H  H  H  H                                                                                 ##STR440## p-Phn                                                                              1 1 1                                   520                                                                              H  t-Bu                                                                             H  H  H  H                                                                                 ##STR441## p-Phn                                                                              1 1 1                                   521                                                                              H  t-Bu                                                                             H  H  H  H                                                                                 ##STR442## 2,5-Pydi                                                                           1 1 1                                   522                                                                              H  TMB                                                                              H  H  H  H                                                                                 ##STR443## p-Phn                                                                              1 1 1                                   523                                                                              H  TMB                                                                              H  H  H  H                                                                                 ##STR444## p-Phn                                                                              1 1 1                                   __________________________________________________________________________

                                      TABLE 22                                    __________________________________________________________________________    Cpd                                                                           No.                                                                              R.sup.2                                                                          R.sup.3 R.sup.4                                                                          R.sup.5                                                                          R.sup.6 R.sup.7 W           Ar     n                      __________________________________________________________________________    524                                                                              Me HOOCCMe.sub.2                                                                         Me Me CMe.sub.2 COOH                                                                        CMe.sub.2 COOH                                                                         ##STR445## p-Phn  1                      525                                                                              Me HOOCCMe.sub.2                                                                         Me Me CMe.sub.2 COOH                                                                        CMe.sub.2 COOH                                                                         ##STR446## 2,5-Pydi                                                                             1                      526                                                                              Me HOOCCMe.sub.2                                                                         Me Me CMe.sub.2 COOH                                                                        CMe.sub.2 COOH                                                                         ##STR447## p-Phn  1                      527                                                                              Me HOOCCMe.sub.2                                                                         Me Me CMe.sub.2 COOH                                                                        CMe.sub.2 COOH                                                                         ##STR448## p-Phn  1                      528                                                                              H  HOOCCMe.sub.2                                                                          .sub.-tBu                                                                       H  CMe.sub.2 COOH                                                                        CMe.sub.2 COOH                                                                         ##STR449## 6-Me-1,3-Phn                                                                         2                      529                                                                              Me H.sub.2 NCOCH.sub.2                                                                   Me Me CH.sub.2 CONH.sub.2                                                                   CH.sub.2 CONH.sub.2                                                                    ##STR450## p-Phn  1                      530                                                                              Me MorCOCH.sub.2                                                                         Me Me CH.sub.2 COMor                                                                        CH.sub.2 COMor                                                                         ##STR451## p-Phn  1                      531                                                                              Me HOOCCH.sub.3                                                                          Me Me CH.sub.2 CONH.sub.2                                                                   CH.sub.2 CONH.sub.2                                                                    ##STR452## p-Phn  1                      532                                                                              Me HOOCCMe.sub.2                                                                         Me Me CH.sub.2 COMor                                                                        CH.sub.2 COMor                                                                         ##STR453## p-Phn  1                      __________________________________________________________________________

                                      TABLE 23                                    __________________________________________________________________________    Cpd                                                                           No.                                                                              R.sup.2                                                                          R.sup.3 R.sup.4                                                                          R.sup.5                                                                          R.sup.6 R.sup.7 W.sub.1     Ar                            __________________________________________________________________________    533                                                                              Me HOOCCH.sub.2                                                                          Me Me H       H                                                                                      ##STR454## p-Phn                         534                                                                              Me HOOCCH.sub.2                                                                          Me Me CH.sub.2 COOH                                                                         H                                                                                      ##STR455## p-Phn                         535                                                                              Me EtOOCCH.sub.2                                                                         Me Me CH.sub.2 COOEt                                                                        CH.sub.2 COOEt                                                                         ##STR456## p-Phn                         536                                                                              Me H       Me Me CH.sub.2 COOH                                                                         H                                                                                      ##STR457## p-Phn                         537                                                                              Me HOOCCMe.sub.2                                                                         Me Me H       H                                                                                      ##STR458## p-Phn                         538                                                                              H  PipCOCH.sub.2                                                                         t-Bu                                                                             H  CH.sub.2 COPip                                                                        H                                                                                      ##STR459## 2,5-Pydi                      __________________________________________________________________________

                                      TABLE 24                                    __________________________________________________________________________    Cpd.                                                                          No.                                                                              R.sup.1                                                                            R.sup.2                                                                          R.sup.3      R.sup.4                                                                           R.sup.5                                                                          R.sup.6 R.sup.7 Ar                             __________________________________________________________________________    539                                                                              Me   Me MeOCH.sub.2 CH.sub.2 OOCCH.sub.2 --                                                        Me  Me H       H       p-Phn                          540                                                                              Me   Me HOOCCH.sub.2 --                                                                            Me  Me H       H       p-Phn                          541                                                                              7,7-DMO                                                                            H  HOOCCMe.sub.2 --                                                                            .sub.- tBu                                                                       H  --CMe.sub.2 COOH                                                                      --CMe.sub.2 COOH                                                                      2,5-Pydi                       542                                                                              Me   Me MeOOCCH.sub.2 --                                                                           Me  Me H       H       p-Phn                          543                                                                              Me   Me 2-HOEt       Me  Me H       H       p-Phn                          544                                                                              Bz   H  CH.sub.3 OCH.sub.2 --                                                                      TMB H  --CMe.sub.2 COOEt                                                                     --CH.sub.2 COOt-Bu                                                                    6-Me-1,3-Phn                   545                                                                              Me   Me H            Me  Me --CH.sub.2 COOH                                                                       --CH.sub.2 COOH                                                                       p-Phn                          __________________________________________________________________________

Compounds of formula (I-25): ##STR460## are as defined in Table 25:

                  TABLE 25                                                        ______________________________________                                        Cpd                                                                           No.     R.sup.1 R.sup.2 R.sup.4                                                                              R.sup.5                                                                            n     W                                   ______________________________________                                        546     Me      Me      Me     Me   1                                                                                    ##STR461##                         547     Me      Me      Me     Me   1                                                                                    ##STR462##                         548     Me      H        .sub.-tBu                                                                           H    1                                                                                    ##STR463##                         549     Me      H        .sub.-tBu                                                                           H    1                                                                                    ##STR464##                         550     Me      Me      Me     Me   2                                                                                    ##STR465##                         551     Me      H        .sub.-tBu                                                                           H    2                                                                                    ##STR466##                         552     Et      Me      Me     Me   1                                                                                    ##STR467##                         553      .sub.-iBu                                                                            Me      Me     Me   1                                                                                    ##STR468##                         554      .sub.-iBu                                                                            Me      Me     Me   1                                                                                    ##STR469##                         555     Pn      Me      Me     Me   1                                                                                    ##STR470##                         556     H       Me      Me     Me   1                                                                                    ##STR471##                         557     Me      H        .sub.-iPr                                                                           H    1                                                                                    ##STR472##                         558      .sub.-iBu                                                                            H        .sub.-tBu                                                                           H    1                                                                                    ##STR473##                         559     Oc      Me      Me     Me   1                                                                                    ##STR474##                         560     Oc      Me      Me     Me   1                                                                                    ##STR475##                         561     Oc      H        .sub.-tBu                                                                           H    1                                                                                    ##STR476##                         562     Oc      H        .sub.-tBu                                                                           H    1                                                                                    ##STR477##                         563     Me      H       TMB    H    1                                                                                    ##STR478##                         564     Me      H       TMB    H    2                                                                                    ##STR479##                         565      .sub.-iBu                                                                            H       TMB    H    1                                                                                    ##STR480##                         566     Oc      H       TMB    H    1                                                                                    ##STR481##                         ______________________________________                                    

Compounds of formula (I-26): ##STR482## are as defined in Table 26:

                  TABLE 26                                                        ______________________________________                                        Cpd.                                                                          No.  R.sup.2 R.sup.103                                                                            R.sup.4                                                                             R.sup.5                                                                            R.sup.106                                                                           W'                                       ______________________________________                                        546  Me      H      Me    Me   H     ═NOCMe.sub.2 COOH                    547  H       H       .sub.- tBu                                                                         H    H     ═NOCH.sub.2 COOH                     548  Me      H      Me    Me   H     ═NOH                                 549  Me      H      Me    Me   H     ═H.sub.2                             550  Me      Et     Me    Me   Et    ═H.sub.2                             ______________________________________                                    

Of the compounds listed above, preferred compounds are Compounds Nos. 5,9, 10, 11, 12, 14, 15, 17, 23, 32, 39, 51, 52, 53, 56, 57, 118, 142,159, 160, 174, 227, 274, 276, 278, 279, 280, 282, 284, 285, 287, 288,301, 302, 305, 307, 401, 403, 405, 410, 412, 425, 428, 429, 461, 462,464, 465, 467, 469, 484, 485, 487, 489, 490, 492, 505, 506, 508, 510,512, 513, 518, 519, 520, 521, and 546. The more preferred compounds areCompounds Nos. 9, 10, 11, 12, 17, 23, 51, 52, 53, 56, 57, 118, 142, 159,160, 174, 274, 284, 401, 405, 410, 461, 464, 467, 508 and 510, and themost preferred compounds are Compounds Nos. 9, 11, 142, 464, 467 and510.

Also preferred are pharmaceutically acceptable salts of the abovecompounds.

The compounds of the invention, which include those compounds having noproviso, may be prepared by reacting a compound of formula (II):##STR483## [in which: R¹, R², R³, R⁴, R⁵, n and Ar are as defined above;

A represents a cyano group, a carboxy group, a C₂ -C₆ alkoxycarbonylgroup, a carbamoyl group or a group of formula -COOM where M representsa cation;

X represents a halogen atom;

R^(7a) represents a hydrogen atom or an unsubstituted C₁ -C₁₀ alkylgroup; and

W² represents a methylene (--CH₂ --) group or a carbonyl (>C═O) group]with thiourea, which has the formula (III): ##STR484## to give acompound of formula (V): ##STR485## (in which: R¹, R², R³, R⁴, R⁵, R⁷¹,n, Ar and W² are as defined above; and

Y represents an oxygen atom or an imino group).

This compound may immediately be hydrolized under the prevailingreaction conditions; if it is not, then a separate hydrolysis step isrequired, to hydrolize the imino group at the 2-position of thethiazolidine ring and, where Y represents an imino group, hydrolize thatimino group also, to an oxygen atom, thereby giving the compound offormula (IV): ##STR486## (in which R¹, R², R³, R⁴, R⁵, R^(7a), n, Ar andW² are as defined above).

If necessary, subsequent steps may be carried out to replace various ofthe substituent groups by other groups within the definitions givenabove, employing the reactions described in more detail hereafter.

Where A represents a C₂ -C⁶ alkoxycarbonyl group (i.e. the alkoxy parthas from 1 to 5 carbon atoms), examples of such groups include themethoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl andbutoxycarbonyl groups. Where A represents a group of formula -COOM and Mrepresents a cation, the nature of the cation is not critical to theinvention, since it is eliminated in the course of the reaction.Preferably the cation is a metal ion, such as a sodium, potassium,calcium or aluminum ion, but it may also be an ammonium ion and otherions, including ions derived from organic bases, are possible, althoughnot presently preferred.

X represents a halogen atom and, again, the nature of this is notcritical, since the atom is eliminated in the course of the reaction.Most suitably, the halogen atom represented by X is a chlorine, bromineor iodine atom.

The reaction of the compound of formula (II) with the thiourea ispreferably effected in the presence of a solvent. The nature of thesolvent is not critical, provided that it has no adverse effect upon thereaction. Suitable solvents include, for example: alcohols, such asmethanol, ethanol, propanol, butanol and ethylene glycol monomethylether; ethers, such as tetrahydrofuran or dioxane; ketones, such asacetone; dimethyl sulfoxide; sulfones, such as sulfolane; and amides,such as dimethylformamide.

There is no criticality as to the molar ratio of the compound of formula(II) to the thiourea and so conventional criteria apply to determine themost suitable proportions. Preferably the two reagents are employed inequimolar amounts or the thiourea is employed in excess, preferably aslight excess. The most suitable ratio of thiourea to compound offormula (II) is from 1:1 to 2:1.

The reaction temperature is not critical to the invention, although theoptimum temperature will vary, depending upon the nature of the reagentsand the solvent employed. In general, we prefer to carry out thereaction at the boiling point of the solvent or at a temperature withinthe range from 80° to 150° C. The time required for the reaction willvary, depending upon many factors, notably the reaction temperature andthe nature of the reagents, but a period of from 1 to 20 hours willnormally suffice.

Where hydrolysis of the resulting compound of formula (V) is required,this may be effected by heating the compound of formula (V) in asuitable solvent in the presence of water and of an acid. The nature ofthe solvent is not critical, provided that it has no adverse effect uponthe reaction and examples of suitable solvents include: sulfolane; andalcohols, such as methanol, ethanol or ethylene glycol monomethyl ether.Suitable acids include such organic acids as acetic acid and suchmineral acids as sulfuric acid or hydrochloric acid. The amount of acidadded is preferably from 0.1 to 10 moles, more preferably from 0.2 to 3moles, per mole of the compound of formula (V). The water or aqueoussolvent employed in this hydrolysis is preferably added instoichiometric excess with respect of the compound of formula (V),preferably a large excess. The reaction temperature is not particularlycritical, although we prefer to carry out the reaction at a temperatureof from 50° to 100° C., at which temperature the reaction will normallybe essentially complete within a period of from 2 to 20 hours.

Where R³ in the compound of formula (V) represents an acyl group, thehydrolysis step will often hydrolize this to a hydrogen atom, giving acompound of formula (IVH): ##STR487## (in which R¹, R² R⁴, R⁵, R^(7a) n,Ar and W² are as defined above); however, depending upon the precisereaction conditions and the nature of the acyl group represented by R³,this hydrolysis may not take place or may take place to a limited extentonly, so that the acyl group is kept intact. Similarly, other acylgroups within the compound of formula (V) may or may not also behydrolized.

Compounds of formula (IV) can exist in the following tautomeric forms:##STR488## although, for convenience, these are represented by a singleformula (IV) herein. It will be appreciated that similar tautomericforms exist in relation to the imino compound of formula (V) and theselikewise are shown herein by means of a single formula only.

Those compounds of the invention which contain one or more carboxygroups or which contain a phenolic hydroxy group [e.g. where R³represents a hydrogen atom, as in the compounds of formula (IVH)] canform salts, in a conventional manner, with cations. There is noparticular restriction on the nature of the cations employed to formsuch salts, except that, where the compounds of the invention are to beused for therapeutic purposes, the resulting salts should bepharmaceutically acceptable, which, as is well-known in the art, meansthat the resulting salts should not have a reduced activity (orunacceptably reduced activity) or an increased toxicity (or unacceptablyincreased toxicity) as compared with the parent compound. On the otherhand, where the compounds are to be used for non-therapeutic purposes,e.g. where they are to be used as intermediates in the preparation ofother compounds, even this restriction does not apply. Suitable saltsinclude, for example: alkali metal salts, such as the sodium, potassiumor lithium salts; alkaline earth metal salts, such as the calcium ormagnesium salts; salts with other metals, especially trivalent metals,for example salts with aluminum, iron, cobalt, nickel or zinc; ammoniumsalts; salts with organic amines, for example the triethylamine orcyclohexylamine salts; and salts with basic amino acids, for examplelysine or arginine.

Likewise, where the compounds of the invention contain a basic group,they can form acid addition salts. As with the salts mentioned above,where the compounds are to be used for therapeutic purposes, the saltsshould be pharmaceutically acceptable but, where they are to be used fornon-therapeutic purposes, this restriction does not apply. Suitableacids for use in producing such salts include: inorganic acids, such ashydrochloric acid, sulfuric acid, nitric acid or phosphoric acid;organic carboxylic acids, such as acetic acid, tartaric acid, maleicacid, fumaric acid, malic acid, glutamic acid or aspartic acid; andorganic sulfonic acids, such as p-toluenesulfonic acid ormethanesulfonic acid.

Furthermore, compounds of formula (IVH) can be converted into acorresponding ester by reaction with an acylating agent, normally anorganic acid or reactive derivative thereof. Suitable reactivederivatives include the acid halides and acid anhydrides, especially theacid anhydrides. Where an acid itself is employed, we prefer to carryout the reaction in the presence, as catalyst, of a strong acid, forexample a mineral acid such as hydrochloric acid or sulfuric acid or anorganic sulfonic acid such as p-toluenesulfonic acid.

Otherwise, the nature of the acylating agent employed depends upon thenature of the acyl group which it is desired to introduce, and these aredefined above as the acyl groups which may be represented by R³.

The reaction is preferably effected in the presence of an solvent, thenature of which is not critical, provided that it has no adverse effectupon the reaction. Suitable solvents include, for example: ethers, suchas diethyl ether, tetrahydrofuran or dioxane; aromatic hydrocarbons,such as benzene or toluene; aliphatic hydrocarbons, such as hexane,cyclohexane or heptane; halogenated hydrocarbons, especially halogenatedaliphatic hydrocarbons, such as methylene chloride or chloroform;ketones, such as acetone or methyl ethyl ketone; amides, such asdimethylformamide or dimethylacetamide; organic bases, such as pyridineor triethylamine; sulfoxides, such as dimethyl sulfoxide; sulfones, suchas sulfolane; water; and mixtures of any two or more thereof. There isno particular restriction on the ratio of the compound of formula (IVH)to the acylating agent, but we generally prefer to employ an excess,suitably a slight excess, of the acylating agent or an equimolar amountof the two reagents. In general, we would employ a molar ratio ofacylating agent to compound of formula (IVH) of from 1:1 to 10:1.

The reaction temperature is not critical and the reaction will takeplace over a wide range of temperatures; however, we generally prefer tocarry out the reaction at a temperature of from 0° C. to 100° C. Thetime required for the reaction will vary widely, depending upon manyfactors, notably the nature of the reagents and the reactiontemperature, but, at a temperature within the recommended range, aperiod of from 5 minutes to 20 hours will normally suffice.

Compounds of the invention in which W represents a hydroxymethylenegroup, that is to say compounds of formula (VI): ##STR489## (in whichR¹, R², R³, R⁴, R⁵, R^(7a), n and Ar are as defined above), can beprepared by reacting a compound of formula (IV) or (IVH) in which W²represents a carbonyl group, that is to say a compound of formula (VII):##STR490## (in which R¹, R², R³, R⁴, R⁵ R^(7a), n and Ar are as definedabove) with a reducing agent, such as sodium borohydride orK-selectride, preferably sodium borohydride. The resulting compound offormula (VI) can exist in the following tautomeric forms: ##STR491##but, for convenience, these are all represented herein by the singleformula (VI).

Reaction of the compound of formula (VII) with the reducing agent ispreferably effected in the presence of a solvent. The nature of thesolvent is not critical, provided that it has no adverse effect upon thereaction. Suitable solvents include, for example: alcohols, such asmethanol, ethanol, propanol, butanol or ethylene glycol monomethylether; and ethers, such as tetrahydrofuran or dioxane. There is also nocriticality as to the ratio of the compound of formula (VII) to thereducing agent, although an excess of the reducing agent is generallypreferred. In general, we prefer to employ a molar ratio of reducingagent to compound of formula (VII) of from 1:1 to 20:1.

The reaction will take place over a wide range of temperatures and theparticular reaction temperature chosen is not particularly critical. Wegenerally prefer to carry out the reaction at a temperature of from 0°C. to 100° C. The time required for the reaction will vary widely,depending upon many factors, notably the reaction temperature and thenature of the reducing agent, but a period of from 1 to 20 hours willnormally suffice.

The resulting compounds of formula (VI) can, if desired, be converted tothe corresponding acyl derivatives of formula (VIII): ##STR492## (inwhich R¹, R², R³, R⁴, R⁵, R^(7a), n and Ar are as defined above, andR^(11a) represents any one of the acyl groups included within thedefinition of R¹¹). These compounds can exist in the followingtautomeric forms: ##STR493## but, for convenience, they are allrepresented herein by a single formula only.

The nature of the reagents, solvent, proportions of reagents andreaction conditions such as temperature and reaction time, are asdescribed above in relation to the acylation of a compound of formula(IVH) to give the corresponding ester. In view of this, depending uponthe precise reaction conditions, where the compound of formula (VI) usedas starting material is a compound in which R³ represents a hydrogenatom, then that hydrogen atom may simultaneously be replaced by an acylgroup to give a compound of formula (VIII) in which both R³ and R^(11a)represent the same acyl group.

Compounds of the invention in which W and U together form acarbon-carbon double bond, that is to say compounds of formula (IX):##STR494## (in which R¹, R², R³, R⁴, R⁵, R^(7a), n and Ar are as definedabove) can be prepared by eliminating water from the above compound offormula (VI) or eliminating an acid R^(11a) OH from the aforementionedcompound of formula (VII). The compounds of formula (IX) can exist invarious tautomeric forms, as illustrated below: ##STR495##

Elimination of water or of the acid R^(11a) OH from the compound offormula (VI) or (VIII) may be effected by contacting in the compoundwith an acid catalyst in a solvent; alternatively, if an acidic solventis employed, then no additional acid catalyst is required.

Suitable acid catalysts include: inorganic acids, such as hydrochloricacid or sulfuric acid; organic carboxylic acids, such as acetic acid;and organic sulfonic acids, such as p-toluenesulfonic acid. The natureof the solvent employed is not critical, provided that it has no adverseeffect upon the reaction. Suitable solvents include, for example:ethers, such as diethyl ether, tetrahydrofuran or dixoane; aromatichydrocarbons, such as benzene, toluene or xylene; aliphatichydrocarbons, such as hexane, cyclohexane or heptane; halogenatedhydrocarbons, especially halogenated aliphatic hydrocarbons, such asmethylene chloride or chloroform; ketones, such as acetone or methylethyl ketone; water; and mixtures of any two or more thereof.

There is no particular restriction on the ratio of the compound offormula (VI) or (VIII) to the acidic catalyst. However, we generallyprefer to employ a molar ratio of said compound to said catalyst of from1:0.001 to 1:1, more preferably from 1:0.01 to 1:0.1.

Where an acidic solvent is to be employed, we prefer to use an organicacid, particularly an organic carboxylic acid, such as acetic acid.

The reaction will take place over a wide range of temperatures, althoughwe generally prefer to employ a temperature of from 0° C. to 100° C. Thetime required for the reaction may vary widely, depending upon manyfactors, notably the nature of the reagents and the reactiontemperature, but a period of from 5 minutes to 20 hours will normallysuffice.

Compounds of formula (IX) may also be prepared by hydrolysis of thecorresponding imino compound of formula (X): ##STR496## (in which R¹,R², R³, R⁴, R⁵, R^(7a), n and Ar are as defined above; and Y is also asdefined above, i.e. it is an oxygen atom or an imino group).

The compound of formula (X) may be prepared from the compound of formula(V) by a series of reactions analogous to those employed to prepare thecompound of formula (IX) from the compound of formula (VII), employingthe same reagents and reaction conditions.

The hydrolysis reaction employed is the same as that employed to convertthe compound of formula (V) into the compound of formula (IV) and may becarried out under the same conditions and employing the same reagents asdescribed in the context of that reaction. As with that reaction, thehydrolysis in this reaction may lead to removal of any acyl grouprepresented by R³ and its replacement by a hydrogen atom, to give acompound of formula (IXH): ##STR497## (in which R¹, R², R⁴, R⁵, R^(7a),n and Ar are as defined above). However, the acyl group may be keptintact by selecting suitable reaction conditions. Also, if desired, theacyl group may be reinstated by an acylation reaction, as describedabove in relation to acylation of the compound of formula (IVH).

Compounds of formula (I) in which W represents a methylene group, thatis to say compounds of formula (XI): ##STR498## (in which R¹, R², R³,R⁴, R⁵, R^(7a), n and Ar are as defined above), may be prepared byhydrogenation of a compound of formula (IX).

This hydrogenation is preferably effected in the presence of a catalyst,for example palladium-on-carbon, Raney nickel or platinum oxide, ofwhich palladium-on-carbon is preferred. The partial pressure of hydrogenis preferably from 1 to 100 atmospheres (about 1 to 101 bars), morepreferably from 1 to 6 atmospheres (about 1 to 6 bars). The reaction ispreferably effected in the presence of a solvent, the nature of which isnot critical, provided that it has no adverse effect upon the reaction.Suitable solvents include, for example: alcohols, such as methanol orethanol; aromatic hydrocarbons, such as benzene or toluene; ethers, suchas tetrahydrofuran; organic acids, such as acetic acid; amides, such asdimethylformamide or dimethylacetamide; water; and mixtures of any twoor more thereof. The reaction will take place over a wide range oftemperatures, but we normally find it convenient to carry out thereaction at a temperature within the range from room temperature to 50°C. The time required for the reaction will vary widely, depending uponmany factors, notably the nature of the reagents and the reactiontemperature, but a period of from 5 minutes to 20 hours will normallysuffice, where a temperature within the recommended range is employed.

Compounds of formula (I) in which W represents a carbonyl group and U,R¹ and the carbon atom to which R¹ is attached together represent agroup of formula --CH═C<, that is to say a compound of formula (XII):##STR499## (in which R², R³ R⁴, R⁵, R^(7a), n and Ar are as definedabove), can be prepared by reacting a compound of formula (XIII):##STR500## (in which R², R³, R⁴, R⁵ R^(7a), A, X, n and Ar are asdefined above and L and U are as defined below) with thiourea, to give acompound of formula (XIV): ##STR501## (in which R², R³, R⁴, R⁵, R^(7a),Y, n and Ar are as defined above and L and U are as defined below) andthen hydrolizing this compound in the presence of an acid to give saidcompound of formula (XII).

In the above formulae, L represents a group of formula -OR³, in which R³is as defined above, and U represents a methylene group; alternatively,U, L and the carbon atom to which the group represented by l isattached, together form a group of formula --CH═C<.

The reactions of the compound of formula (XIII) with thiourea and thehydrolysis of the compound of formula (XIV) thus produced to give thedesired compound of formula (XII) are similar to the reactions of thecompound of formula (II) with thiourea to give the compound of formula(V) and the hydrolysis of this to give the compound of formula (IV) andmay be carried out employing the same reagents and under the samereaction conditions.

Compounds of formulae (X), (IXH), (XI), (XII) and (XIV) exist astautomeric forms, analogous to those already described above in relationto compounds of formulae (IV), (VI), (VIII) and (IX), although all suchtautomers are represented herein by a single formula only, forconvenience.

Compounds of formula (I) in which W represents a group of formula>C═N-OR^(12a), that is to say compounds of formula (XV): ##STR502## (inwhich: R¹, R², R³, R⁴, R⁵, R^(7a), U, n and Ar are as defined above; andR^(12a) represents a hydrogen atom, a C₁ -C₁₀ alkyl group or asubstituted C₁ -C₁₀ alkyl group, as defined for R¹²), can be prepared byreacting the corresponding compound in which W represents a carbonylgroup, that is to say a compound of formula (XVI): ##STR503## (in whichR¹, R², R³, R⁴, R⁵, R^(7a), U, n and Ar are as defined above) with ahydroxylamine derivative of formula (XVII):

    H.sub.2 N-OR.sup.12a                                       (XVII)

(in which R^(12a) is as defined above) or a salt thereof.

The compounds of formulae (XV) and (XVI) can exist in tautomeric forms,for example as follows in relation to the compound of formula (XV):##STR504## however, for convenience, these are represented herein by asingle formula only.

The nature of the hydroxylamine derivative of formula (XVII) dependsupon the nature of the group ═NOR^(12a) which it is desired to introduceinto the compound. The hydroxylamine derivative may be employed in theform of a salt thereof, for example a salt with a mineral acid, such ashydrochloric acid or sulfuric acid.

The reaction may be effected in the presence of an acid-binding agent.Where an acid-binding agent is employed, it is preferably an alkalimetal hydroxide (such as potassium hydroxide) or an alkali metalcarbonate (such as sodium carbonate or potassium carbonate).

The reaction is preferably effected in the presence of a solvent, thenature of which is not critical, provided that it has no adverse effectupon the reaction. Examples of suitable solvents include: alcohols, suchas methanol, ethanol, propanol, butanol or ethylene glycol monomethylether; ethers, such as tetrahydrofuran or dioxane; amides, such asdimethylformamide or dimethylacetamide; sulfoxides, such as dimethylsulfoxide; sulfones, such as sulfolane; organic bases, such astriethylamine or pyridine; water; and mixtures of any two or morethereof.

There is no particular limitation on the molar ratio of thehydroxylamine derivative of formula (XVII) to the compound of formula(XVI) and the reaction will take place at any molar ratio. However, wegenerally prefer to employ an excess of the hydroxylamine derivative,preferably a large excess, with respect to the compound of formula(XVI). A preferred molar ratio of the hydroxylamine derivative (XVII) tothe compound of formula (XVI) is from 1:1 to 50:1.

If an acid addition salt of the hydroxylamine derivative (XVII) isemployed, then we prefer to carry out the reaction in the presence of anacid-binding agent. The amount of acid-binding agent is not critical andan amount less than equimolar with respect to the salt of thehydroxylamine derivative can be employed.

The reaction will take place over a wide range of temperatures and theparticular temperature chosen is not critical. We prefer to carry outthe reaction at a temperature within the range from 0° C. to 100° C. Thetime required for the reaction will vary widely, depending upon manyfactors, notably the nature of the reagents and the reactiontemperature, but, at temperatures within the preferred range givenabove, a period of from 5 minutes to 10 days will normally suffice.

Compounds of formula (I) in which W represents a group of formula>C═N-O-R^(12b) (in which R^(12b) represents any one of the acyl groupsdefined for R¹²), that is to say compounds of formula (XVIII):##STR505## (in which R¹, R², R³, R⁴, R⁵, R^(7a), R^(12b), U, n and Arare as defined above), may be prepared by reacting the correspondingcompound of formula (XV) in which R^(12a) represents a hydrogen atom,that is to say a compound of formula (XIX): ##STR506## (in which R¹, R²,R³, R⁴, R⁵, R^(7a), U, n and Ar are as defined above) with an acylatingagent, preferably an acid halide or acid anhydride, especially an acidanhydride.

The compounds of formula (XVIII) can exist in the form of tautomers,analogous to those defined above in relation to the other similarcompounds. However, for convenience, these tautomers are all representedherein by a single formula (XVIII).

The acylation reaction of this compound of formula (XIX) to give thecompound of formula (XVIII) is essentially the same as the reactionemployed to acylate the compound of formula (IVH) and may be carried outunder the same conditions and employing the same reagents, solvents etcas described heretofore in relation to that acylation reaction.

The compounds of the invention in which W represents a group of formula>C═N-OR¹² (in which R¹² is as defined above), that is to say the oxime,oxime ether and oxime ester compounds, i.e. compounds of formulae (XV),(XVIII) and (XIX), can exist in both the syn and anti forms, and bothforms are included within the scope of the present invention. Theseoxime, oxime ether and oxime ester compounds can be converted into theirsalts by conventional means. As with the salts described previously,there is no particular limitation on the nature of the salt, providedthat, where the salt is to be employed for therapeutic purposes, itshould be pharmaceutically acceptable. Suitable salts include: alkalimetal salts, such as the sodium or potassium salt; alkaline earth metalsalts, such as the calcium salt; and salts with trivalent metals, suchas the aluminum salt. However, other salts, including those other onesdescribed above can also be formed.

Compounds of the invention in which R⁶ and/or R⁷ represents an alkylgroup or substituted alkyl group, i.e. compounds of formula (XX):##STR507## (in which R¹, R², R³, R⁴, R⁵, W, U, n and Ar are as definedabove; and R^(6b) and R^(7b) are the same or different and eachrepresents a hydrogen atom, a C₁ -C₁₀ alkyl group or a substituted C₁-C₁₀ alkyl group, as defined in relation to R⁶ and R⁷, provided thatR^(6b) and R^(7b) do not both represent hydrogen atoms), can be preparedby reacting a compound of formula (XXI): ##STR508## (in which R¹, R²,R³, R⁴, R⁵, R^(7a), W, U, n and Ar are as defined above) with an alkylhalide or substituted alkyl halide of formula (XXII):

    R.sup.20 X                                                 (XXII)

(in which R²⁰ represents R^(6b) or R^(7b) and X represents a halogenatom, for example a fluorine, chlorine, bormine or iodine atom,preferably a chlorine or bromine atom.

The reaction is preferably effected in the presence of an acid-bindingagent. The purpose of the acid-binding agent is to remove from thereaction system the hydrogen halide HX produced by the reaction and anycompound capable of doing this may be employed. Examples of suitableacid-binding agents include: alkali metal carbonates, such as sodiumcarbonate or potassium carbonate; alkali metal hydroxides, such assodium hydroxide or potassium hydroxide; alkali metal bicarbonates, suchas sodium bicarbonate or potassium bicarbonate; alkaline earth metalhydroxides, such as calcium hydroxide; alkali metal hydrides, such assodium hydride or potassium hydride; alkali metal alkoxides, such assodium methoxide or sodium ethoxide; organic lithium compounds, such asbutyllithium or t-butyllithium; lithium dialkylamides, such as lithiumdiisopropylamide or lithium dicyclohexylamide; and organic bases, suchas pyridine or triethylamine. Of these, the alkali metal carbonates,especially potassium carbonate, are preferred.

The relative proportions of the base and the compound of formula (XXI)are not particularly critical and may vary over a wide range. Forexample, a molar ratio of base to compound (XXI) of from 0.5:1 to 20:1is preferred, more preferably from 1:1 to 10:1.

The reaction is preferably effected in the presence of a solvent, thenature of which is not critical, provided that it has no adverse effectupon the reaction. Suitable solvents include, for example: ketones, suchas acetone or methyl ethyl ketone; ethers, such as diethyl ether,tetrahydrofuran or dioxane; aromatic hydrocarbons, such as benzene,toluene or xylene; aliphatic hydrocarbons, such as hexane, heptane orcyclohexane; amides, such as dimethylformamide or dimethylacetamide;sulfoxides, such as dimethyl sulfoxide; sulfones, such as sulfolane;halogenated hydrocarbons, especially halogenated aliphatic hydrocarbons,such as methylene chloride, chloroform or (1,2-dichloroethane; organicbases, such as pyridine or triethylamine; water; and mixtures of any twoor more thereof.

The molar ratio of the compound of formula (XXI) to the alkyl halide offormula (XXII) is not particularly critical but, in order to ensure thatthe reaction goes to completion, we prefer to employ an excess of thealkyl halide. In general, the molar ratio of the alkyl halide to thecompound of formula (XXI) is from 0.5:1 to 20:1, more preferably from1;1 to 10:1. Where only a group R^(6b) is to be introduced into thecompound, a still more preferred molar ratio is from 1:1 to 5:1, mostpreferably from 1:1 to 3:1. Where both groups R^(6b) and R^(7b) are tobe introduced, the more preferred ratio is from 1:1 to 10:1 and the mostpreferred ratio is from 3:1 to 6:1.

The reaction will take place over a wide range of temperatures and theparticular reaction temperature is not particularly critical. Wegenerally prefer to carry out the reaction at a temperature of from -10°C. to +100° C., more preferably from 15° to 40° C. The time required forthe reaction may vary widely, depending upon many factors, notably thereaction temperature and the nature of the reagents, however, at atemperature within the preferred range, a period of from 10 minutes toseveral days, more commonly from 1 hour to 4 days, will normallysuffice.

Where only R^(6b) is to be introduced, a preferred reaction temperatureis from 0° to 100° C., more preferably from 15° to 40° C. At such atemperature, the reaction time will normally be from 10 minutes toseveral hours, commonly from 30 minutes to 3 hours.

Where both R^(6b) and R^(7b) are to be introduced, a preferred reactiontemperature is from 0° to 100° C., more preferably from 15° to 40° C. Atsuch a temperature, the reaction time will normally be from 10 minutesto several days, commonly from 5 hours to 2 days.

The reaction normally takes place preferentially at the nitrogen atom atthe 3-position of the thiazolidine ring and, accordingly, where thequantity of alkyl halide (XXII) is restricted, the principal productwill normally be a compound in which the alkyl or substituted alkylgroup has been introduced at that position. Where R^(7a) represents ahydrogen atom in the compound of formula (XXI), it is possible toreplace this by an alkyl or substituted alkyl group by this reactionand, provided sufficient alkyl halide (XXII) is employed, disubstitutionwill take place.

Where a compound in which R⁶ and/or R⁷ represents a carboxyalkyl groupis required, we prefer to employ a compound of formula (XXII) in whichR²⁰ represents an alkoxycarbonylalkyl or substituted alkoxycarbonylalkylgroup, to give the corresponding compound of formula (XX) where R^(6b)and/or R^(7b) represents that alkoxycarbonylalkyl or substitutedalkoxycarbonylalkyl group. The resulting compound of formula (XX) maythen be hydrolized to remove the alkoxy or substituted alkoxy part ofthis alkoxycarbonylalkyl group and give a free carboxyalkyl group. Ingeneral, particularly where W is >CH₂ or >C═O, the hydrolysis reactionemployed is similar to the hydrolysis employed to convert the compoundof formula (V) to a compound of formula (IV) and may be carried outunder the same reaction conditions and employing the same reagents. Inthe case of lower alkyl, e.g. ethyl or t-butyl, esters, the free acidmay be formed at a relatively low temperature, e.g. from 0° to 5° C., bytreatment with an aqueous alkali, e.g. alkali metal hydroxide, such assodium hydroxide. In the case of alkoxyalkyl esters, e.g. theZ-methoxyethyl esters, the reaction is preferably effected at a highertemperature in the presence of an acid. As with the previously describedhydrolysis reaction, there is a possibility that the hydrolysis may alsohydrolize any acyl group represented by R³ in the compound of formula(XX) to give a compound (XXI) in which R³ represents a hydrogen atom.However, this may be avoided by appropriate choice of reagents andreaction conditions.

Compounds of the invention in which R³ represents a sulfo (HSO₃ -) groupor an esterified sulfo group of formula -SO₃ R⁸, i.e. compounds offormula (XXIII): ##STR509## (in which R¹, R², R⁴, R⁵, R⁶, R⁷, R⁸, W, U,n and Ar are as defined above), may be prepared by reacting thecorresponding compound of formula (I) in which R³ represents a hydrogenatom, e.g. a compound of formula (IVH) or (IXH), with a correspondinghalosulfonic acid or halosulfonate of formula (XXIV):

    XSO.sub.2 OR.sup.8                                         (XXIV)

(in which R⁸ and X are as defined above).

The reaction is similar to the reaction to introduce an alkyl orsubstituted alkyl group R^(6b) or R^(7b) into a compound of formula(XXI) and may be carried out under the same conditions and employing thesame solvents and acid-binding agents.

In all of the compounds of the invention, the carbon atom at the5-position of the thiazolidine ring is asymmetric. Moreover, when R¹represents an atom of a group (i.e. it does not, together with U, form adouble bond), the carbon atom at the 2-position of the chroman ring isasymmetric. When W represents a group of formula >CH-OR¹¹, then thecarbon atom at the 4-position of the chroman ring is also asymmetric. Itwill, therefore, be appreciated that a variety of isomers of thecompounds of the invention are possible, as a result of differentconfigurations of substituent groups about these asymmetric carbonatoms. Although all such isomers are represented herein by a singleformula only, the present invention envisages both the individualisolated isomers and mixtures thereof. The compounds of the inventionmay be produced in the form of individual isomers by using an isolatedisomer as the starting material or by stereospecific synthesistechniques. Alternatively, the compounds may be produced as a mixture ofsuch isomers, in which case they may be employed in the form of such amixture or the individual isomers may be separated by conventionalresolution techniques.

The compounds of the invention obtained by any of the reactionsdiscussed above may be isolated and purified by conventional techniques,including any one or more of the following: concentration; evaporationof solvent under reduced pressure; extraction with a solvent;crystallization and recrystallization; solvent transfer; chromatographytechniques, especially column chromatography and thin layerchromatography; and optical resolution.

The α-halocarboxylic acid derivatives of formula (II) employed asstarting materials in the processes of the present invention can beprepared by a variety of methods, for example as follows.

Method A

Method A is the method described in more detail in copending U.S. patentapplication Ser. No. 644,996 and prepares compounds where W and U bothrepresent methylene groups, that is to say compounds of formula (XXX),as illustrated in the following reaction scheme: ##STR510##

In the above formulae, R¹ -R⁵, R^(7a), Ar, n, A and X are as definedabove, n'=(n-1); and R³⁰ represents a hydroxy-protecting group.

Step A1

The chroman carboxylic acid homologs (XXXI), which are the startingmaterials for this Method, may be prepared as described, for example, inthe Journal of the American Oil Chemists Society, 51, 200 (1974).

These acids (XXXI) are reduced with a reducing agent, such as lithiumaluminum hydride or Vitride [sodium bis(2-methoxyethoxy)aluminumhydride], to give the corresponding chroman alcohol homolog (XXXII).This reaction is preferably effected in the presence of a solvent, thenature of which is not critical, provided that it does not interferewith the reaction. Suitable solvents include: ethers, such as diethylether, tetrahydrofuran or ethylene glycol dimethyl ether; aromatichydrocarbons, such as benzene, toluene or xylene; and aliphatichydrocarbons, such as hexane, heptane, cyclohexane, petroleum ether,ligroin or ethylcyclohexane.

The ratio of the amount of acid (XXXI) to reducing agent is notparticularly critical, but we generally prefer to use a slight molarexcess of reducing agent. Preferably the amount of reducing agent isfrom 1 to 2 moles per mole of acid (XXXI). The reaction conditions,particularly the reaction temperature and time, will vary depending uponmany factors, such as the nature of the starting material, the reducingagent and the solvent, but the reaction is generally carried out at atemperature of from 0° to 100° C. At such a temperature, a reactionperiod of from 10 minutes to 20 hours will normally suffice.

Alternatively, the chroman alcohol homolog (XXXII) may be prepared byreacting a hydroquinone with a compound of formula (XXXV): ##STR511##(in which n and R¹ are as defined above), especially the compound offormula (XXXV) where R¹ represents a methyl group, in the presence ofaluminum chloride, as described in West German Patent No. 3,010,504.

Step A2

The chroman alcohol homologs of formula (XXXII) obtained in Step A1 maybe converted to the corresponding nitrophenoxyalkyl chroman compounds(XXXIII). However, before carrying out this reaction, we prefer that thephenolic hydroxy group should be protected by a hydroxy-protecting groupR³⁰.

The nature of the hydroxy-protecting group is not critical and any suchgroup commonly used in this type of reaction and compound may beemployed. Suitable groups include: alkoxyalkyl groups, such as themethoxymethyl group; alkoxycarbonylalkyl groups, such as theethoxycarbonylmethyl, t-butoxycarbonylmethyl,1-methoxycarbonyl-1-methylethyl and 1-(t-butoxycarbonyl)-1-methylethylgroups; aralkyl groups, such as the benzyl group; the2-tetrahydropyranyl group; and acyl groups, such as the acetyl orbenzoyl groups. The alkoxyalkyl, alkoxycarbonylalkyl and2-tetrahydropyranyl groups are preferred. The reaction is normallyeffected by contacting a compound R³⁰ X (in which R³⁰ is as definedabove and X represents a halogen atom, preferably a chlorine atom), suchas methoxymethyl chloride, ethoxycarbonylmethyl bromide,1-(t-butoxycarbonyl)-1-methylethyl bromide, benzoyl chloride or benzylchloride, more preferably methoxymethyl chloride or benzoyl chloride,with the compound of formula (XXXII) in the presence of a base such asan alkali metal or alkaline earth metal hydride (e.g. sodium hydride orcalcium hydride) or an alkali metal alkoxide (e.g. sodium methoxide,sodium ethoxide or potassium t-butoxide). The reaction is normallycarried out in the presence of a solvent, for example: an ether, such asdiethyl ether, tetrahydrofuran or dioxane; an aromatic hydrocarbon, suchas benzene, toluene or xylene; an aliphatic hydrocarbon, such as hexaneor heptane; an amide, such as dimethylformamide or dimethylacetamide; asulfoxide, such as dimethyl sulfoxide; or a sulfone, such as sulfolane.There is no particular limitation on the molar ratio of compound (XXXII)to the compound R³⁰ X. In general, we prefer to employ from about 0.8 to1.2 mole of the compound R³⁰ X per mole of the compound (XXXII). Thereaction conditions, particularly the reaction temperature and time, mayvary depending upon a number of factors, especially the natures of thestarting material, the compound R³⁰ X and the solvent, but we normallyprefer a reaction temperature of from 0° to 50 ° C. and a time of fromseveral minutes to several tens of minutes.

The protection chroman alcohol produced by this reaction can, ifdesired, be isolated and purified, but it may be, and preferably is,converted to the nitrophenoxyalkylchroman compound of formula (XXXIII)without intermediate isolation.

Conversion to the compound of formula (XXXIII) is effected by reactingthe protected compound (XXXII) with a halonitroaryl compound, e.g. a 4-or 3-halonitrobenzene, of formula X-(AR)-NO₂ (in which X and Ar are asdefined above) in the presence of a base, such as sodium hydride, in asolvent, such as dimethyl sulfoxide or dimethylformamide. The amount ofhalonitroaryl compound employed is preferably about 2 moles per mole ofprotected compound (XXXII). The reaction temperature is preferably from30° to 100° C. and the time required for the reaction is usually fromseveral minutes to several hours.

Sept A3

The nitro compound of formula (XXXIII) thus obtained is reduced in thisstep to the corresponding amino compound of formula (XXXIV). In thecourse of or before or after this reduction, the protecting groups R³⁰may be allowed to remain as it is, removed or converted to another group(particularly an acyl group, such as an acetyl or benzoyl group).

When deprotection of the compound (XXXIII) is desired, this can easilybe achieved by reacting the compound (XXXIII) with a dilute aqueous acid(such as hydrochloric acid, sulfuric acid or nitric acid) to hydrolysethe protecting group. The reaction is normally carried out in thepresence of a solvent, for example: an alcohol, such as methanol,ethanol or propanol; an ether, such as tetrahydrofuran or dioxane; aketone, such as acetone or methyl ethyl ketone; an organic acid, such asacetic acid or propionic acid; dimethyl sulfoxide; dimethylformamide; orwater. Of these, water or an organic acid is preferred. The amount ofacid used for hydrolysis is preferably from 0.01 to 5 moles, morepreferably from 0.01 to 1 mole, per mole of the compound (XXXIII). Weprefer to carry out the reaction in the presence of a large molar excessof water or of acetic acid as the solvent. The reaction temperature ispreferably from ambient temperature to 100° C. and the time required forthe reaction is normally from several minutes to about 20 hours.

If it is desired to convert the protecting group R³⁰ to another group,particularly an acyl group, this may be achieved by acylation of thedeprotected compound obtained as described above. The acylating agentmay be an acid halide, such as acetyl chloride or benzoyl chloride, oran acid anhydride, such as acetic anhydride. This reaction is preferablycarried out in the presence of an organic amine (such as pyridine ortriethylamine) or in the presence of an inorganic base (for example analkali metal hydroxide, such as sodium hydroxide or potassium hydroxide,or an alkali metal carbonate or bicarbonate, such as sodium carbonate,potassium carbonate or sodium bicarbonate). The acylating reaction ispreferably carried out in the presence of a solvent, for example: analiphatic hydrocarbon, such as hexane, cyclohexane, heptane, ligroin orethylcyclohexane; an aromatic hydrocarbon, such as benzene, toluene orxylene; an organic amine, such as pyridine or triethylamine; a ketone,such as acetone or methyl ethyl ketone; an amide, such asdimethylformamide; a sulfoxide, such as dimethyl sulfoxide; or water.The ratio of the amount of deprotected compound (XXXIII) to acylatingagent is not particularly critical, however, a slight molar excess ofacylating agent is usually preferred, for example from 1 to 1.5 moles ofacylating agent per mole of deprotected compound (XXXIII). Where anorganic amine is employed as the acid-binding agent, it may be employedin any amount from 1 mole to a large molar excess per mole of thecompound of formula (XXXIII). Where an inorganic base is employed as theacid-binding agent, it is preferably employed in an amount of from 1 to10 moles per mole of the compound of formula (XXXIII). The reactionconditions, particularly the reaction temperature and time, may varydepending upon a number of factors, particularly the natures of thestarting material and solvent employed, but the reaction is preferablyeffected at a temperature of from 0° to 100° C. for a period of fromseveral minutes to 20 hours.

The nitro compound of formula (XXXIII) (which may optionally have beensubjected to any of the processes described above) is then reduced tothe amino compound of formula (XXXIV). The reduction may be a catalyticreduction process employing hydrogen, or reduction with a metal (Such aszinc or iron) and an acid (which may be a mineral acid such ashydrochloric acid or sulfuric acid or an organic acid such as aceticacid). Preferably a catalytic reduction process is employed. Thecatalyst employed for this catalytic reduction is preferablypalladium-on-carbon, Raney nickel or platinum oxide, of whichpalladium-on-carbon is particularly preferred. The hydrogen pressure ispreferably from 1 to 100 atmospheres (about 1 to 101 bars), morepreferably from 1 to 6 atmospheres (about 1 to 6 bars). The reaction ispreferably effected in the presence of a solvent, the nature of which isnot critical, provided that it has no adverse effect upon the reaction.Suitable solvents include: alcohols, such as methanol or ethanol;aromatic hydrocarbons, such as benzene or toluene; ethers, such astetrahydrofuran; organic acids, such as acetic acid; water; or mixturesof any two or more thereof. The reaction conditions, particularly thereaction temperature and time, may vary depending upon a number offactors, particularly the nature of the starting material, the methodemployed for reduction and the solvent, but the reaction is normallyeffected at a temperature from ambient temperature to 50° C. and theperiod required for the reaction is generally from several minutes toabout 20 hours.

Step A4

The chroman derivative of formula (XXXIV), prepared as described in stepA3 above, is diazotized and then subjected to a Meerwein arylation, togive the desired α-halocarboxylic acid compound of formula (XXX). Thetwo reactions are preferably effected sequentially in the same reactionsystem.

The diazotization reaction comprises reacting the amino compound offormula (XXXIV) with a nitrite (such as sodium nitrite) in the presenceof an acid, such as hydrochloric acid or hydrobromic acid.

The Meerwein arylation reaction comprises reacting the resultingdiazonium compound with an acrylic compound of formula CH₂ ═CR^(7a) A(in which R^(7a) and A are as defined above), e.g. acrylic acid, anacrylic or methacrylic acid ester (such as methyl acrylate, ethylacrylate or ethyl methacrylate) or another acrylic acid derivative (suchas acrylonitrile, acrylamide, methacrylonitrile or methacrylamide), inthe presence of a catalytic amount of a cuprous compound (which may be asalt, such as cuprous chloride, or another cuprous compound such ascuprous oxide). The acrylic and methacrylic acid esters are preferredand the preferred cuprous compound is cuprous oxide.

The reactions are preferably effected in the presence of a solvent, thenature of which is not critical, provided that it does not interferewith the reactions. Suitable solvents include: alcohols, such asmethanol or ethanol; ketones, such as acetone or methyl ethyl ketone;water; or a mixture of any two or more thereof. The molar ratio of theamino compound of formula (XXXIV) to the acrylic acid or derivativethereof of formula CH₂ ═CR^(7a) A is preferably from 1:1 to 1:15, morepreferably from 1:5 to 1:10. The molar ratio of the amino compound(XXXIV) to the cuprous compound is preferably from 1:0.01 to 1:1, morepreferably from 1:0.03 to 1:0.3. The reaction conditions, particularlythe reaction temperature and time, may vary depending upon a number offactors, especially the natures of the starting materials and thesolvent employed, but the reaction is normally carried out at atemperature from ambient temperature to 100° C., preferably from 30° to60° C., and the period required for the reaction is normally from about20 minutes to about 20 hours, more preferably from 30 minutes to 2hours.

Method B

This method may also be used to prepare compounds of formula (II) inwhich both W and U represent methylene groups and is especially usefulfor preparing compounds in which n is 2. The reactions involved areillustrated in the following reaction scheme: ##STR512##

In the above reaction scheme, R¹ -R⁵ are as defined above, R³¹represents an alkyl group and Me represents the methyl group.

In this reaction, the chroman alcohol of formula (XXXIIa) or its analogsin which n is an integer other than 2, may be prepared from thehydroquinone derivative of formula (XXXVI) via the sequence of stepsindicated as steps B1, to give the compound of formula (XXXVIII),followed by step B2, and then step B3 (analogous to step A1 1 of MethodA), according to the method described in the Journal of the American OilChemists Society, 51, 200 (1974). Alternatively, it can be synthesizedin a single step by reacting the hydroquinone derivative (XXXVI) withthe dihydropyran derivative of formula (XXXVII), as illustrated in stepB4 by the method described in Japanese Patent Application Kokai No.201775/83. Subsequently, the resulting compound of formula (XXXIIa) maybe subjected to steps A2, A3 and A4, to give the desired compound offormula (XXX).

Method C

This method is also useful for synthesizing compounds of formula (II) inwhich both W and U represent methylene groups. This method may becarried out as illustrated by the following reaction scheme: ##STR513##

In the above formulae, R², R⁴, R⁵ and R³⁰ are as defined above; R^(1a)represents any one of the groups heretofore defined for R¹, other thanthe hydrogen atom; and R³² represents a hydrogen atom or acarboxy-protecting group, preferably an alkyl, alkenyl, alkynyl, aralkylor optionally substituted phenyl group, more preferably a C₁ -C₄ alkylgroup.

Steps C1-C4

These steps are carried out essentially as described in the Journal ofMedicinal Chemistry, 18, 934 (1975).

Step C5

In this step, the phenolic hydroxy group is, if required, protected. Weprefer that this hydroxy group should be protected prior to step C6.Examples of protecting groups R³⁰ have been given above in relation toMethod A and the method of introducing the protecting group is also asdescribed above in relation to step A2. However, in this step, we preferto employ the compound R³⁰ X in excess, preferably a molar ratio of thecompound R³⁰ X to the compound of formula (XLIII) of from 1:1 to 2:1.The reaction is preferably effected at a temperature of from 0° to 50°C., more preferably from 10° to 25° C. The time required for thereaction will vary, depending upon many factors, but a period of fromseveral minutes to several hours will normally suffice. The resultingcompound of formula (XLIV) may then be used in step C6 withoutintermediate isolation.

Step C6

In this step, a chromancarboxylic acid derivative of formula (XLV)having a protected hydroxy group at the 6-position and a group R^(1a) atthe 2-position is prepared. This may be achieved by reacting thecompound of formula (XLIV) with a base in an inert solvent in order togenerate a carbanion and then reacting this carbanion with a compound offormula R^(1a) X¹ (in which R^(1a) is as defined above and X¹ representsa halogen atom, for example a chlorine, bromine or iodine atom, or asulfonyloxy group, for example a methanesulfonyloxy, ethanesulfonyloxy,benzenesulfonyloxy or p-toluenesulfonyloxy group).

Any base may be employed in the reaction to generate the carbanion, andexamples of such bases include: organic lithium compounds, such asmethyllithium, butyllithium, t-butyllithium or phenyllithium; lithiumdialkylamides, such as lithium diisopropylamide, lithiumdicyclohexylamide or lithium N-isopropyl-N-cyclohexylamide; and alkalimetal hydrides, such as lithium hydride, sodium hydride or potassiumhydride. Of these, we prefer the organic lithium compounds and lithiumdialkylamides.

The reaction is preferably effected in the presence of a solvent, thenature of which is not critical, provided that it has no adverse effectupon the reaction. Suitable solvents include, for example, ethers, suchas diethyl ether, tetrahydrofuran or dioxane.

The reaction temperature employed for generation of the carbanion ispreferably relatively low, e.g. from -78° C. to room temperature. Thetemperature employed for reaction of this anion with the compound offormula R^(1a) X¹ is preferably somewhat higher, e.g. from 0° C. to 60°C. The time required for these reactions will vary widely, dependingupon many factors, notably the nature of the reagents and the reactiontemperature, but a period of from 30 minutes to 2 hours will normallysuffice for generation of the carbanion, whilst a period of from 1 to 24hours will normally suffice for the subsequent reaction with thecompound R^(1a) X¹.

Thereafter, the resulting compound of formula (XLV) may be subjected tothe same reactions as described in Method A, to give the resultingcompound of formula (XXX).

If desired, Step C6 may be omitted, to prepare a compound in which R¹ isa hydrogen atom.

Method D

This method is also described in copending U.S. patent application Ser.No. 644,996 and prepares compounds of formula (II) in which U representsa methylene group and W represents a carbonyl group, that is to saycompounds of formula (LI), by the reactions summarized in the followingreaction scheme: ##STR514##

In the above formulae, R¹ -R⁵, R^(7a), Ar, n, A and X are as definedabove. The reaction sequence comprises the following steps:

Step D1

The acetophenone derivative of formula (XLVII) which is one of thestarting materials for this step may be prepared, for example, asdescribed in Chem. Berichte, 95, 1413. The other starting material, thenitroaryloxyalkyl alkyl ketone of formula (XLVIII), may be prepared, forexample, as described in J. Med. Chem., 21, 386 (1978) and J. Am. Chem.Soc., 99, 7653 (1977).

In this step, the compounds (XLVII) and (XLVIII) are reacted together inthe presence of a secondary amine, as described, for example, inJapanese Patent Application Kokai No. 19670/77.

The reaction is preferably effected in the presence of a solvent, thenature of which is not critical, provided that it has no adverse effectupon the reaction. Suitable solvents include: aliphatic and aromatichydrocarbons, such as petroleum ether, benzene, toluene, xylene, hexaneand cyclohexane; halogenated aliphatic and aromatic hydrocarbons, suchas carbon tetrachloride, methylene chloride, chloroform, chlorobenzeneand dichlorobenzene; ethers, such as diethyl ether, tetrahydrofuran anddioxane; amides, such as dimethylformamide, dimethylacetamide andN-methylpyrrolidone; alcohols, such as methanol, ethanol and ethyleneglycol monomethyl ether; esters, such as ethyl acetate; nitriles, suchas acetonitrile; and sulfoxides, such as dimethyl sulfoxide.

The secondary amine employed in this reaction is preferably a compoundof formula R^(a) -NH-R^(b), in which R^(a) and R^(b) may be the same ordifferent and each represents an alkyl group, or R^(a) and R^(b),together with the nitrogen atom to which they are attached, represent anitrogen-containing heterocyclic ring system. Examples of such secondaryamines include diethylamine, dimethylamine, N-methylpiperazine,pyrrolidine, piperidine or morpholine, of which pyrrolidine isparticularly preferred.

The molar ratio of the compound of formula (XLVII) to the compound offormula (XLVIII) is not particularly critical, but, to avoid waste,roughly equimolar amounts of the two compounds are used. In general, theamount of secondary amine is preferably from 0.05 to 1.5 moles, morepreferably from 0.1 to 1 mole, per mole of the compound of formula(XLVII) or (XLVIII).

The reaction conditions particularly reaction temperature and time, mayvary depending upon a number of factors, especially the nature of thestaring materials and of the solvent, but, in general, we prefer tocarry out the reaction at a temperature of from -30° C. to +150° C.,more preferably from 10° to 120° C., for a period of from 30 minutes to3 days.

Step D2

In this step, the nitro compound of formula (XLIX) prepared as in stepD1 is reduced t the corresponding amino compound of formula (L). Thisreaction is precisely the same as step A3 of Method A, employing thesame reaction conditions and reagents.

Step D3

In this step, the amino compound of formula (L), obtained as describedin step D2, is diazotized and then subjected to a Meerwein arylation, togive the desired α-halocarboxylic acid derivative of formula (LI). Thesereactions are precisely the same as those described in step A4 of MethodA and may be carried out employing the same reagents and reactionconditions.

Method E

This method may be used for preparing compounds of formula (II) in whichW represents a carbonyl group and U represents a methylene group, andwhere there is a group R^(1a) (as defined above) at the 2-position ofthe chroman ring. The reactions involved are summarized in the followingreaction scheme: ##STR515##

In the above formulae, R^(1a), R², R⁴, R⁵, R³⁰, R³² and Ar are asdefined above. R³³ represents a carbonyl-protecting group, examples ofwhich are described in more detail below.

Step E1

In this step, the starting material of formula (XLII), which may havebeen prepared as described in step C3 of Method C, is subjected toreduction, but under milder conditions than employed in step C4, so thatonly the double bond between the 2- and 3-positions is hydrogenated.

The reaction is preferably effected by catalytic hydrogenation. Suitablecatalysts include palladium-on-carbon, Raney nickel and platinum oxide,of which palladium-on-carbon is preferred. The reaction is preferablyeffected employing a partial pressure of hydrogen of from 1 to 100atmospheres (about 1 to 101 bars), more preferably from 1 to 6atmospheres (about 1 to 6 bars). The reaction is preferably effected inthe presence of a solvent, the nature of which is not critical, providedthat it has no adverse effect upon the reaction. Suitable solventsinclude, for example: alcohols, such as methanol or ethanol; aromatichydrocarbons, such as benzene or toluene; ethers, such astetrahydrofuran; amides, such as dimethylformamide or dimethylacetamide;organic carboxylic acids, such as acetic acid; water; and mixtures ofany two or more thereof.

The reaction will take place over a wide range of temperatures, but weprefer to employ a temperature of from room temperature to 50° C., morepreferably from room temperature to 40° C. The time required for thereaction will vary widely, depending upon many factors, notably thenature of the reagents and the reaction temperature; however, at atemperature within the preferred range described above, the reactionwill normally be complete within a period of from several minutes toseveral days, commonly from 30 minutes to 20 hours.

Step E2

In this step, the carbonyl group at the 4-position of the chromancompound of formula (LII) prepared in step E1 is protected; it isdesirable that this protection should be carried out prior to thealkylation reaction of step E4.

There is no particular limitation on the nature of the protecting groupemployed and any such group commonly used for protecting carbonyl groupsmay equally well be used in the present invention. For example, the oxocompound may be converted into a protected enol compound, such as anenol ether or enol ester. Alternatively, it may be converted into aketone acetal having cyclic or non-cyclic side chains or into a ketonedithioacetal. Conversion into a ketone dithioacetal is preferred.

Preferably, R³³ represents a group of formula -B¹ -B² -B¹ -, where B¹represents an oxygen or sulfur atom (preferably a sulfur atom) and B²represents a group of formula --(CH₂)₂ -, --(CH₂)₃ --, --(CH₂)₄ -- or--CH₂ --CH═CH--CH₂ -(cis), preferably --(CH₂)₂ -- or --(CH₂)₃ -- andmore preferably --(CH₂)₃ --. Such a protected compound may be preparedby reacting the compound of formula (LII) with a compound of formulaH-B¹ -B² -B¹ -H (in which B¹ and B² are as defined above), for exampleethylene glycol, 1,3-propanediol, 1,2-ethanedithiol, 1,3-propanedithiolor cis-2-butene-1,4-diol, preferably 1,3-propanedithiol, underdehydrating conditions. The reaction may take place in the presence orabsence of a catalyst. Where a catalyst is employed, suitable catalystsinclude, for example: Lewis acids, such as boron trifluoride and diethylether and acetic acid complexes thereof, or aluminum chloride; inorganicacids, such as hydrogen chloride or sulfuric acid; organic carboxylicacids, such as acetic acid, tartaric acid, fumaric acid or maleic acid;and organic sulfonic acids, such as p-toluenesulfonic acid ormethanesulfonic acid. We prefer to use a Lewis acid, more preferably aboron trifluoride acetic acid complex salt.

The reaction does not always require a solvent; however, if a solvent isemployed, its nature is not critical, provided that it has no adverseeffect upon the reaction. Examples of suitable solvents include:aromatic hydrocarbons, such as benzene or xylene; and halogenatedhydrocarbons, especially halogenated aliphatic hydrocarbons, such aschloroform or methylene chloride. Of these, we prefer halogenatedhydrocarbons, such as chloroform.

There is no particular limitation on the proportions of the compound offormula (LII) to the compound of formula H-B¹ -B² -B¹ -H; however, asmall excess of H-B¹ -B² -B¹ -H is preferred, preferably a molar ratioof the compound H-B¹ -B² -B¹ -H to the compound of formula (LII) of from1:1 to 2:1. Equally, there is no particular limitation on theproportions of catalyst employed. However, a molar ratio of catalyst tocompound of formula (LII) of from 1:1 to 1:4 is preferred.

The reaction will take place over a wide range of temperatures, but wegenerally prefer to carry out the reaction at a temperature of from 0°to 100° C., more preferably from 10° C. to 40° C. The time required forthe reaction may vary widely, depending upon the nature of the reagentsand the reaction temperature, but a period of from several minutes toseveral days, more commonly from 1 hour to 30 hours, will normallysuffice.

Step E3

In this step, the phenolic hydroxy group at the 6-position of thechroman ring is protected, typically by reaction with a compound offormula R³⁰ X (in which R³⁰ and X are as defined above). This reactionis similar to the reactions described in steps A2 and C5 and ispreferably carried out employing the same reagents and under thereaction conditions described in relation to step C5. The resultingcompound of formula (LIV) may be isolated from the reaction mixture ormay be used without intermediate isolation directly in step E4.

Step E4

In this step, the compound of formula (LIV) is converted to a carbanionand then reacted with a compound of formula R^(1a) X¹ (in which R^(1a)and X¹ are as defined above). This reaction is similar to that describedabove in relation to step C6 and may be carried out employing the samereagents and under the same reaction conditions as employed in step C6.

If it is desired to prepare a compound in which R¹ represents a hydrogenatom, step E4 may be omitted, and the product of step E3--the compoundof formula (LIV)--may be employed directly in step E5.

Step E5

In this step, the chroman-2-carboxylic acid derivative of formula (LV)is reduced to the corresponding alcohol of formula (LVI). This reactionis essentially the same as that described above in step A1 of the MethodA and may be carried out under the same conditions and employing thesame reagents. However, in this case, we prefer to employ a temperaturewithin the range from -50° C. to +120° C.

Step E6

In this step, a group of formula -(Ar)-NO₂ (Ar being as defined above)is introduced into the compound of formula (LVI) prepared as describedin step E5. This reaction may be effected by reacting the compound offormula (LVI) with a base to convert it to the corresponding alkoxide,and then reacting this with a compound of formula X-(Ar)-NO₂ (in which Xand Ar are as defined above).

Any base capable of forming an alkoxide with the compound of formula(LVI) may be employed. Examples include: alkali metal and alkaline earthmetal hydrides, such as sodium hydride or calcium hydride; and alkalimetal alkoxides, such as sodium methoxide, sodium ethoxide or potassiumt-butoxide. Of these, we prefer sodium hydride or sodium ethoxide. Theproportions of the compound of formula (LVI) and the base are notparticularly critical; however, we prefer to employ a slight excess ofthe base, preferably a molar ratio of base to compound of formula (LVI)of from 1:1 to 2:1.

The reactions are preferably effected in the presence of a solvent, thenature of which is not critical, provided that it has no adverse effectupon the reaction. Suitable solvents include, for example: ethers, suchas diethyl ether, tetrahydrofuran or dioxane; aromatic hydrocarbons,such as benzene, toluene or xylene; aliphatic hydrocarbons, such ashexane or heptane; amides, such as dimethylformamide ordimethylacetamide; sulfoxides, such as dimethyl sulfoxide; and sulfones,such as sulfolane. Of these, the amides are preferred. The relativeproportions of the compound of formula X-(Ar)-NO₂ to the compound offormula (LVI) are not particularly critical to the present invention,however, we prefer to employ a slight excess of the compound of formulaX-(Ar)-NO₂, preferably a molar ratio of said compound of formulaX-(Ar)-NO₂ to compound of formula (LVI) of from 1:1 to 10:1.

The reaction will take place over a wide range of temperatures, but wegenerally prefer to employ a temperature of from 30° C. to 100° C. Thetime required for the reaction may vary widely, depending upon manyfactors, notably the nature of the reagents and the reactiontemperature. A period of from several minutes to several hours willnormally suffice.

The nitro compound of formula (LVII) thus obtained may then be convertedto the desired compound of formula (XXX) by following steps A3 and A4 asdescribed in Method A. At some stage in the course of this, theprotected carbonyl group at the 4-position of the chroman system isdeprotected and this may be carried out as described hereafter in StepE7.

Step E7

In this step, the protected carbonyl group is deprotected. Anyconventional reaction employed to deprotect a protected carbonyl groupmay be employed in this step. For example, the protected compound may bereacted with: a protonic acid, such as hydrochloric acid or sulfuricacid; a Lewis acid, such as boron trifluoride or an ether, e.g. diethylether, or acetic acid complex thereof, or aluminum chloride; when B¹represents a sulfur atom, a heavy metal salt, heavy metal oxide, heavymetal peroxide or a mixture of any two or three of these, for example asilver, cadmium, mercurous, mercuric, cuprous or thallic chloride,bromide, iodide, nitrate, perchlorate, oxide or peroxide; iodine; asulfuryl halide, such as sulfuryl chloride; or an N-haloimide, such asN-chlorosuccinimide or N-bromosuccinimide. Of these, we prefer mercuricchloride, mercuric oxide or a mixture thereof, more preferably a mixtureof mercuric chloride and mercuric oxide.

The reaction is preferably effected in the presence of a solvent, thenature of which is not critical, provided that it has no adverse effectupon the reaction. Suitable solvents include, for example: alcohols,such as methanol, ethanol, propanol or isopropanol; ketones, such asacetone or methyl ethyl ketone; halogenated hydrocarbons, especiallyhalogenated aliphatic hydrocarbons, such as chloroform, methylenechloride or 1,2-dichloroethane; ethers, such as tetrahydrofuran ordioxane; organic carboxylic acids, such as acetic acid; nitriles, suchas acetonitrile; water; and mixtures of any two or more thereof.

The proportions of the compound of formula (LVII) or other protectedcompound to the deprotecting agent are not critical. However, we preferto employ a slight excess of the deprotecting agent, e.g. a molar ratioof deprotecting agent to compound of formula (LII) or other protectedcompound of from 1:1 to 10:1, more preferably from 1:1 to 4:1.

The reaction will take place over a wide range of temperatures, but wegenerally find it convenient to carry out the reaction at a temperaturewithin the range from room temperature to 100° C., more preferably from40° C. to 80° C. The time required for the reaction will vary, dependingupon many factors, notably the nature of the reagents and the reactiontemperature; however, at a temperature within the ranges mentionedabove, a period of from several minutes to several hours, more commonlyfrom 30 minutes to 4 hours, will normally suffice.

Thereafter, the compound of formula (LVIII) may be subjected to steps A3and A4 to give the desired compound of formula (XXX). Alternatively, thedeprotection step E7 may take place after or between these steps A3 andA4.

Method F

A particularly preferred process for preparing compounds of formula (II)in which both W and U represent methylene groups is illustrated in thefollowing reaction scheme: ##STR516##

In the above formulae, R¹ -R⁵ n and Ar are as defined above and R^(11a)represents any one of the acyl groups defined above in relation to R¹¹.

STEP F1

In this step, a 4-oxochroman derivative of formula (XLIX), which mayhave been prepared by a variety of the methods described above,including, for example step E7 of Method E or step D1 of Method D, isreduced to the corresponding 4-hydroxy compound of formula (LIX). Anyreducing agent capable of reducing an oxo group on a saturated ringsystem to a hydroxy group may be employed. We generally prefer to employsodium borohydride or K-selectride, of which sodium borohydride isparticularly preferred.

The reaction is preferably effected in the presence of a solvent, thenature of which is not critical, provided that it has no adverse effectupon the reaction. Suitable solvents include, for example: alcohols,such as methanol, ethanol, propanol, butanol or ethylene glycolmonomethyl ether; and ethers, such as tetrahydrofuran or dioxane.

There is no particular limitation on the relative proportions of thecompound of formula (XLIX) to the reducing agent, e.g. sodiumborohydride, but we generally prefer to employ an excess, preferably aslight excess, of the reducing agent. In general, we would use a molarratio of reducing agent to compound of formula (XLIX) of from 1:1 to20:1.

The reaction will take place over a wide range of temperatures and theexact temperature chosen is not particularly critical. A temperaturewithin the range from 0° C. to 100° C. is generally preferred. The timerequired for the reaction may vary widely, depending upon many factors,notably the nature of the reagents and the reaction temperature.However, a period of from 1 to 20 hours will normally suffice.

Step F2

In this optional step, the compound of formula (LIX) prepared asdescribed in step F1 is acylated. The acylating agent employed ispreferably an acid halide or acid anhydride.

The reaction is preferably carried out in the presence of a solvent, thenature of which is not critical, provided that it does not interferewith the reaction. Suitable solvents include, for example: ethers, suchas diethyl ether, tetrahydrofuran or dioxane; aromatic hydrocarbons,such as benzene, toluene or xylene; aliphatic hydrocarbons, such ashexane, cyclohexane or heptane; halogenated hydrocarbons, especiallyhalogenated aliphatic hydrocarbons, such as methylene chloride orchloroform; organic bases, such as pyridine or triethylamine; amides,such as dimethylformamide or dimethylacetamide; sulfoxides, such asdimethyl sulfoxide; and sulfones, such as sulfolane.

There is no particular limitation on the proportions of compound offormula (LIX) to the acylating agent, but we generally prefer to useequimolar amounts or a slight excess of acylating agent. In general, amolar ratio of acylating agent to compound of formula (LIX) of from 1:1to 10:1 is preferred. Where R³ in the compound of formula (LIX) is ahydrogen atom, the group R³ O may also be acylated in the course of thisreaction.

The reaction will take place over a wide range of temperatures and theparticular temperature chosen is not critical. We generally prefer tocarry out the acylation reaction at a temperature within the range from0° C. to 100° C. The time required for the reaction may vary over a widerange, depending upon many factors, notably the nature of the reagentsand the reaction temperature; however, at a temperature within thepreferred range, a period of from 5 minutes to 20 hours will normallysuffice.

Step F3

In this step, which is an alternative to step F2, a 2H-chromene compoundof formula (LXI) is prepared by dehydrating the 4-hydroxychroman (LIX).

The dehydration reaction may be achieved in the presence or absence of adehydrating agent or dehydrating catalyst. Suitable dehydrating agentsand catalysts include, for example: inorganic acids, such ashydrochloric acid, sulfuric acid, nitric acid or phosphoric acid;organic carboxylic acids, such as acetic acid, tartaric acid or maleicacid; organic sulfonic acids, such as p-toluenesulfonic acid,naphthalenesulfonic acid or methanesulfonic acid; inorganic salts, suchas ammonium chloride or calcium chloride; phosphorus pentoxide;polyphosphoric acid; silica gel; and alumina. Of these, we prefer anorganic carboxylic acid such as acetic acid or an organic sulfonic acid,such as p-toluenesulfonic acid.

It is not always necessary to employ a solvent in this reaction;however, where a solvent is used, its nature is not particular critical,provided that is does not interfere with the reaction. Examples ofsuitable solvents include: alcohols, such as methanol, ethanol orisopropanol; ketones, such as acetone or methyl ethyl ketone; ethers,such as diethyl ether, tetrahydrofuran or dioxane; aromatichydrocarbons, such as benzene, toluene or xylene; aliphatichydrocarbons, such as hexane, cyclohexane or heptane; halogenatedhydrocarbons, especially halogenated aliphatic hydrocarbons, such asmethylene chloride or chloroform; organic carboxylic acids, such asacetic acid or propionic acid; organic bases, such as pyridine ortriethylamine; amides, such as dimethylformamide or dimethylacetamide;sulfoxides, such as dimethyl sulfoxide; sulfones, such as sulfolane;water; and mixtures of any two or more thereof. Of these, we preferaromatic hydrocarbons, such as benzene, or organic acids, such as aceticacid.

If a dehydrating agent or catalyst is employed, the relative proportionof such agent or catalyst to the compound of formula (LIX) is notcritical, but we prefer to employ a molar ratio of said agent orcatalyst to said compound of formula (LIX) of from 0.01:1 to 10:1, morepreferably from 0.1:1 to 3:1.

The reaction will take place over a wide range of temperatures and theexact temperature chose is not particularly critical; however, wegenerally prefer to carry out the reaction at a temperature in the rangefrom 20° C. to 100° C. The time required for the reaction will vary,depending upon many factors, notably the nature of the reagents and thereaction temperature; however, at temperatures within the preferredrange indicated above, a period of from several minutes to 20 hours willnormally suffice.

Step F4

In this step, the 2H-chromene compound of formula (LXI) is prepared fromthe 4-acyloxychroman of formula (LX) by elimination of an acid offormula R^(11a) OH (in which R^(11a) is as defined above).

This elimination reaction can be carried out in the presence or absenceof an acid-binding agent or catalyst. Examples of suitable such agentsand catalysts include: inorganic acids, such as hydrochloric acid,sulfuric acid, nitric acid or phosphoric acid; organic carboxylic acids,such as acetic acid, tartaric acid or maleic acid; organic sulfonicacids, such as p-toluenesulfonic acid; naphthalenesulfonic acid ormethanesulfonic acid; inorganic salts, such as ammonium chloride orcalcium chloride; organic bases, such as pyridine or triethylamine;silica gel; and alumina. Of these, we prefer an organic carboxylic orsulfonic acid, such as acetic acid or p-toluenesulfonic acid.

It is not always necessary to employ a solvent for this eliminationreaction and, where a solvent is employed, its nature is not critical,provided that it has no adverse effect on the reaction. Suitablesolvents include, for example: alcohols, such as methanol, ethanol orisopropanol; ketones, such as acetone or methyl ethyl ketone; ethers,such as deithyl ether, tetrahydrofuran or dioxane; aromatichydrocarbons, such as benzene, toluene or xylene; aliphatichydrocarbons, such as hexane, cyclohexane or heptane; halogenatedhydrocarbons, such as methylene chloride or chloroform; organic acids,such as acetic acid or propionic acid; organic bases, such as pyridineor triethylamine; amides, such as dimethylformamide ordimethylacetamide; sulfoxides, such as dimethyl sulfoxide; sulfones,such as sulfolane; and water. Of these, we prefer aromatic hydrocarbons(such as benzene) or organic acids (such as acetic acid).

Where an acid-binding agent or catalyst is employed, the relativeproportions of such agent or catalyst and the compound of formula (LX)are not particularly critical. We generally prefer to employ the agentor catalyst and the compound of formula (LX) in a molar ratio of from0.01:1 to 10:1, more preferably from 0.1:1 to 3:1.

The reaction will take place over a wide range of temperatures and theexact temperature chosen is not particularly critical. In general, weprefer to carry out the reaction at a temperature within the range from0° C. to 120° C., more preferably from 40° C. to 100° C. The timerequired for the reaction may vary widely, depending upon many factors,notably the nature of the reagents and the reaction temperature;however, at a temperature within the preferred ranges indicated above, aperiod of from several minutes to several days, commonly from 10 minutesto 10 hours, will normally suffice.

Step F5

In this step, the chroman derivative of formula (XXXIV) is prepared bythe reductive hydrogenation of the 2H-chromene derivative of formula(LXI).

Catalytic hydrogenation is preferably employed. Suitable catalystsinclude, for example palladium-on-carbon, Raney nickel or platinumoxide, of which palladium-on-carbon is preferred. The partial pressureof hydrogen may vary widely, for example from 1 to 100 atmospheres(about 1 to 101 bars), more preferably from 1 to 6 atmospheres (about 1to 6 bars). The reaction is preferably effected in the presence of asolvent, the nature of which is not critical, provided that it does notinterfere with the reaction. Suitable solvents include, for example:alcohols, such as methanol or ethanol; aromatic hydrocarbons, such asbenzene or toluene; ethers, such as tetrahydrofuran; organic acids, suchas acetic acid; water; or a mixture of any two or more thereof.

The reaction will take place over a wide range of temperatures and theexact temperature chosen is not particularly critical; however, wegenerally prefer to carry out the reaction at a temperature from roomtemperature to 50° C. The time required for the reaction may varywidely, depending upon many factors, notably the nature of the reagentsand the reaction temperature; however, at a temperature within theindicated range, a period of from several minutes to 20 hours willnormally suffice.

The α-halocarboxylic acid derivative of formula (XXX) may then beprepared as described in step A4 from this compound of formula (XXXIV).

Steps F1, F3 (or F2+F4), F5, A4 and the final step for reacting theα-halocarboxylic acid derivative (XXX) with thiourea to give the desiredthiazolidine derivative of the invention can, if desired, be carried outin succession without intermediate isolation of the products of any ofthese steps.

Moreover, these steps are not necessarily carried out in the sequencedescribed above and they may be carried out in any appropriate order.For example, one suitable alternative sequence would comprise: first,reducing the nitro group in the compound of formula (XLIX) by a stepanalogous to step F5 to give the corresponding amino compound; reducingthe carbonyl group at the 4-position of the chroman ring by a stepanalogous to step F1 to give a 4-hydroxychroman compound; dehydratingthis 4-hydroxychroman compound by a step analogous to step F3 (oracylating and then eliminating the acid by steps analogous to steps F2and F4), to give a 2H-chromene compound; and finally hydrogenating the2H-chromene compound by a step analogous to step F5.

Method G

This process is useful for converting a chroman derivative, such asthose prepared in steps E5 and E6 of Method E, having a carbonyl groupas W at the 4-position to the corresponding compound where W is amethylene group. The compounds prepared as described in steps E5 and E6are first, if necessary, deprotected, to remove the protecting group R³⁰at the 6-position. The resulting free hydroxy group is then acylated.

The resulting compound then has its carbonyl group protected, asdescribed in step E2, to give a compound of formula (LXIII) or (LXV).These compounds are then hydrogenated, to give the correspondingcompounds of formulae (LXIV) or (LXVI), as shown below: ##STR517##

In the above formulae, R¹ -R⁵ and Ar are as defined above; s is 2, 3 or4.

The hydrogenation is preferably effected in the presence of a catalyst,preferably a nickel catalyst, such as Raney nickel.

The hydrogen partial pressure may vary widely, for example from 1 to 100atmospheres (about 1 to 101 bars), more preferably from 1 to 6atmospheres (about 1 to 6 bars).

The reaction is preferably effected in the presence of a solvent, thenature of which is not critical, provided that it has no adverse effectupon the reaction. Suitable solvents include, for example: alcohols,such as methanol or ethanol; aromatic hydrocarbons, such as benzene ortoluene; ethers, such as tetrahydrofuran; organic acids, such as aceticacid; water; and mixtures of any two or more thereof.

The reaction will take place over a wide range of temperatures, forexample from room temperature to 50° C. The time required for thereaction will vary, depending upon many factors, notably the nature ofthe reagents and the reaction temperature, but a period of from severalminutes to 20 hours will normally suffice.

The resulting compounds of formulae (LXIV) and (LXVI) may thereafter betreated by any of the appropriate processes described above to give thedesired compounds of formula (II).

Method H

This method can be used to prepare compounds of formula (XIII), having agroup L at the 2-position of the chroman ring and where W is a carbonylgroup, as illustrated in the following reaction scheme: ##STR518##

In the above formulae, R² -R⁵, U, L, n, Ar, R^(7a), X and A are asdefined above.

Preferably, L represents a group of formula -OR³ and U represents amethylene group. However, if desired, L, the carbon atom to which it isattached and U may together represent a double bond.

Step H1

In this step, the compound of formula (XLVII) is reacted with a compoundof formula (LXX):

    O.sub.2 N--(Ar)--O--(CH.sub.2).sub.n --COX                 (LXX)

(in which Ar, n and X are as defined above), followed by treatment withan organic base, such as sodium ethoxide or potassium t-butoxide. Thereaction is otherwise similar to that of step C2 of Method C and may becarried out under the same reaction conditions.

Step H2

This is equivalent to step A3 and may be carried out using the samereagents and under the same reaction conditions.

Step H3

This is equivalent to step A4 of Method A and may be carried out usingthe same reagents under the same reaction conditions.

Of Methods A-H, Methods A, B, C, D, E, F and H are preferred, Methods A,C, D, E, F and H being more preferred and a combination of Methods D, Fand A being most preferred. A particularly preferred combination ofreactions comprises steps F1, F3 or F2 plus F4), F5, A4 and finallyreaction with thiourea to give a compound of formula (I) in which R⁷ isR^(7a) and R⁶ is a hydrogen atom. In particular, we prefer this sequenceof steps where Ar represents a p-phenylene group.

In the compounds of formula (II), the carbon atom at the 2-position ofthe chroman ring and the carbon atom to which the substituents X, A andR^(7a) are attached are both asymmetric and accordingly a number ofisomers are possible. The present invention envisages both theindividual isolated isomers as well as mixtures thereof. Individualisomers may be prepared by stereospecific synthesis techniques or byseparation of mixtures of isomers. Alternatively, the mixtures ofisomers may be employed as such.

We have found that the α-halocarboxylic acid derivatives of formula (II)have the ability to lower the levels of blood lipid peroxides, bloodtriglycerides and blood cholesterol, indicating that, in addition totheir use as intermediates in the preparation of the compounds of theinvention, they may also have in themselves therapeutic value in thetreatment of hyperlipemia.

The compounds of formula (II) prepared as described above can, ifdesired, be converted to various of their hydrolysis products or may betransesterified or converted to salts, for example such metal salts asthe sodium, potassium, calcium or aluminum salts. Alternatively, theycan be converted from metal salts or from compounds having freehdyroxyphenyl groups or free carboxy groups to derivatives thereof, forexample as follows:

Compounds in which R³ represents a hydrogen atom and A represents acarboxy group can be prepared by hydrolysis of the correspondingcompound of formula (II) in which, for example, R³ represents an acylgroup and A represents an alkoxycarbonyl group. This reaction ispreferably effected in the presence of a base, for example: an inorganicbase, such as an alkali metal carbonate (e.g. sodium carbonate orpotassium carbonate) or an alkali metal hydroxide (e.g. sodium hydroxideor potassium hydroxide); or an organic base, such as an alkali metalalkoxide (e.g. sodium methoxide, sodium ethoxide or potassiumt-butoxide). The reaction is preferably effected in the presence of asolvent, the nature of which is not critical, provided that it has noadverse effect upon the reaction. Suitable solvents include: loweralcohols, such as methanol or ethanol; ethers, such as tetrahydrofuranor dioxane; water; or mixtures of any two or more thereof.

The molar ratio of the compound of formula (II) to the base ispreferably from 1:1 to 1:5, more preferably from 1:2 to 1:3. Althoughthe reaction conditions, particularly the reaction temperature and time,may vary depending upon a number of factors, particularly the natures ofthe starting material, base and solvent employed, the reaction isgenerally carried out at a temperature of from -10° C. to +30 C., morepreferably from 0° C. to 10° C., and the reaction time is generally fromseveral minutes to several tens of hours.

The compound of formula (II) in which R³ represents a hydrogen atom andA represents an alkoxycarbonyl group can be prepared by solvolysis ofthe corresponding compound in which R³ represents an acyl group and Arepresents an alkoxycarbonyl group. This is carried out in the presenceof a base, preferably an alkali metal alkoxide, such as sodiummethoxide, sodium ethoxide or potassium t-butoxide. The reaction ispreferably effected in the presence of a solvent, for example: analcohol, such as methanol, ethanol, propanol, isopropanol or t-butanol;an ether, such as tetrahydrofuran or dioxane; or a mixture of any two ormore thereof. It the alkoxycarbonyl group represented by A in thestarting material is to be kept intact, it is preferred that the alkalimetal alkoxide should be the alkoxide corresponding to thisalkoxycarbonyl group and that the solvent should be an alcohol, whichlikewise corresponds to the alkoxycarbonyl group. However, thealkoxycarbonyl group in the starting material may, if desired, beconverted into any other alkoxycarbonyl group by suitable choice of thealkali metal alkoxide and the alcohol solvent.

The molar ratio of the compound of formula (II) to the base ispreferably from 1:1 to 1:3, more preferably from 1:1 to 1:2. Thereaction conditions, especially the reaction temperature and reactiontime, may vary, depending upon a number of factors, particularly thenatures of the starting materials, bases and solvents employed, but thereaction is preferably carried out at a temperature of from -10° C. to+30° C., more preferably from 0° to 10° C., for a period of from severalminutes to several tens of hours.

Compounds of formula (II) in which R³ represents an acyl group and Arepresents a carboxy group may be prepared by hydrolysis of thecorresponding compound of formula (II) in which R³ represents an acylgroup and A represents an alkoxycarbonyl group. In this case, thehydrolysis is effected in the presence of an inorganic base (for examplean alkali metal carbonate, such as sodium carbonate or potassiumcarbonate, or an alkali metal hydroxide, such as sodium hydroxide orpotassium hydroxide) or in the presence of another base such as analkali metal alkoxide (for example sodium methoxide, sodium ethoxide orpotassium t-butoxide). This reaction is preferably effected in thepresence of a solvent, for example: a lower alcohol, such as methanol orethanol; an ether, such as tetrahydrofuran or dioxane; water; or amixture of any two or more thereof. The molar ratio of the compound offormula (II) to the base is preferably from 1:1 to 1:5, more preferablyfrom 1:1 to 1:2. The reaction conditions, particularly the reactiontemperature and time, may vary depending upon a number of factors,especially the natures of the starting materials, bases and solventsemployed, but the reaction is normally effected at a temperature of from-10° C. to +30° C., more preferably from 0° to 10° C. for a period offrom several minutes to several tens of hours.

Of the compounds of formula (II) which exhibit the therapeutic effectsmentioned above and which also form part of the present invention,preferred compounds are those listed below in Table 27.

In this Table, the abbreviations used are as previously defined inrelation to Tables 1-26.

Compounds of formula (II-27): ##STR519## are as defined in Table 27:

                                      TABLE 27                                    __________________________________________________________________________    Cpd. No.                                                                           R.sup.1                                                                            R.sup.2                                                                          R.sup.3  R.sup.4                                                                           R.sup.5                                                                          W    n Ar     X A                                __________________________________________________________________________    1001 Me   Me H        Me  Me                                                                                ##STR520##                                                                        1 6-Me-1,3-Phn                                                                         Cl                                                                              COOEt                            1002 Me   Me Ac       Me  Me                                                                                ##STR521##                                                                        1 6-Me-1,3-Phn                                                                         Cl                                                                              COOEt                            1003 Me   Me H        Me  Me                                                                                ##STR522##                                                                        1 6-Me-1,3-Phn                                                                         Cl                                                                              COOEt                            1004 Me   Me Ac       Me  Me                                                                                ##STR523##                                                                        1 6-Me-1,3-Phn                                                                         Cl                                                                              COOEt                            1005 Me   Me H        Me  Me                                                                                ##STR524##                                                                        1 2,5-Pydi                                                                             Cl                                                                              COOEt                            1006 Me   Me Ac       Me  Me                                                                                ##STR525##                                                                        1 2,5-Pydi                                                                             Cl                                                                              COOEt                            1007 Me   Me H        Me  Me                                                                                ##STR526##                                                                        1 2,5-Pydi                                                                             Cl                                                                              COOEt                            1008 Me   Me Ac       Me  Me                                                                                ##STR527##                                                                        1 2,5-Pydi                                                                             Cl                                                                              COOEt                            1009 Me   H  H         .sub.- t-Bu                                                                      H                                                                                 ##STR528##                                                                        1 6-Me-1,3-Phn                                                                         Cl                                                                              COOEt                            1010 Me   H  Ac        .sub.- t-Bu                                                                      H                                                                                 ##STR529##                                                                        1 6-Me-1,3-Phn                                                                         Cl                                                                              COOEt                            1011 Me   H  H         .sub.- t-Bu                                                                      H                                                                                 ##STR530##                                                                        1 6-Me-1,3-Phn                                                                         Cl                                                                              COOEt                            1012 Me   H  Ac        .sub.- t-Bu                                                                      H                                                                                 ##STR531##                                                                        1 6-Me-1,3-Phn                                                                         Cl                                                                              COOEt                            1013 Me   H  H         .sub.- t-Bu                                                                      H                                                                                 ##STR532##                                                                        1 2,5-Pydi                                                                             Cl                                                                              COOEt                            1014 Me   H  Ac        .sub.- t-Bu                                                                      H                                                                                 ##STR533##                                                                        1 2,5-Pydi                                                                             Cl                                                                              COOEt                            1015 Me   H  H         .sub.- t-Bu                                                                      H                                                                                 ##STR534##                                                                        1 2,5-Pydi                                                                             Cl                                                                              COOEt                            1016 Me   H  Ac        .sub.- t-Bu                                                                      H                                                                                 ##STR535##                                                                        1 2,5-Pydi                                                                             Cl                                                                              COOEt                            1017 Me   H  Ac       TMB H                                                                                 ##STR536##                                                                        1 p-Phn  Cl                                                                              COOEt                            1018 Me   H  Ac       TMB H                                                                                 ##STR537##                                                                        1 p-Phn  Cl                                                                              COOEt                            1019 Me   H  Ac       TMB H                                                                                 ##STR538##                                                                        1 6-Me-1,3-Phn                                                                         Cl                                                                              COOEt                            1020 Me   H  Ac       TMB H                                                                                 ##STR539##                                                                        1 6-Me-1,3-Phn                                                                         Cl                                                                              COOEt                            1021 Me   H  Ac       TMB H                                                                                 ##STR540##                                                                        1 2,5-Pydi                                                                             Cl                                                                              COOEt                            1022 Me   H  Ac       TMB H                                                                                 ##STR541##                                                                        2 p-Phn  Cl                                                                              COOMe                            1023 Et   Me Boz      Me  Me                                                                                ##STR542##                                                                        1 5-Me-1,3-Phn                                                                         Cl                                                                              COOH                             1024  .sub.- iBu                                                                        Me 4-MeBoz  Me  H                                                                                 ##STR543##                                                                        1 2,5-Pydi                                                                             Cl                                                                              COOHN.sub.4                      1025  -nPn                                                                              Me Ac       Me  Me                                                                                ##STR544##                                                                        1 2,5-Pydi                                                                             Cl                                                                              COOMe                            1026 Hx   Me Ac       Me  Me                                                                                ##STR545##                                                                        1 p-Phn  Cl                                                                              COOEt                            1027  .sub.- iHx                                                                        Me Ac       Me  Me                                                                                ##STR546##                                                                        1 p-Phn  Cl                                                                              COOMe                            1028 Hx   Me Ac       Me  Me                                                                                ##STR547##                                                                        1 6-Me-1,3-Phn                                                                         Cl                                                                              COOH                             1029 Hp   H  H         .sub.- tBu                                                                       H                                                                                 ##STR548##                                                                        1 2,5-Pydi                                                                             Cl                                                                              COOEt                            1030 Oc   Me Ac       Me  Me                                                                                ##STR549##                                                                        1 p-Phn  Cl                                                                              COOEt                            1031 Oc   Me Ac       Me  Me                                                                                ##STR550##                                                                        1 p-Phn  Cl                                                                              COOEt                            1032 Oc   Me Ac       Me  Me                                                                                ##STR551##                                                                        1 6-Me-1,3-Phn                                                                         Cl                                                                              COOEt                            1033 Oc   Me Ac       Me  Me                                                                                ##STR552##                                                                        1 6-Me-1,3-Phn                                                                         Cl                                                                              COOEt                            1034 Oc   Me Ac       Me  Me                                                                                ##STR553##                                                                        1 2,5-Pydi                                                                             Cl                                                                              COOEt                            1035 Oc   Me Ac       Me  Me                                                                                ##STR554##                                                                        1 2,5-Pydi                                                                             Cl                                                                              COOEt                            1036 Oc   H  Ac        .sub.- t-Bu                                                                      H                                                                                 ##STR555##                                                                        1 p-Phn  Cl                                                                              COOEt                            1037 Oc   H  Ac        .sub.- t-Bu                                                                      H                                                                                 ##STR556##                                                                        1 p-Phn  Cl                                                                              COOEt                            1038 Oc   H  Ac        .sub.- t-Bu                                                                      H                                                                                 ##STR557##                                                                        1 6-Me-1,3-Phn                                                                         Cl                                                                              COOEt                            1039 Oc   H  Ac        .sub.- t-Bu                                                                      H                                                                                 ##STR558##                                                                        1 6-Me-1,3-Phn                                                                         Cl                                                                              COOEt                            1040 Oc   H  Ac        .sub.- t-Bu                                                                      H                                                                                 ##STR559##                                                                        1 2,5-Pydi                                                                             Cl                                                                              COOEt                            1041 Oc   H  Ac        .sub.- t-Bu                                                                      H                                                                                 ##STR560##                                                                        1 2,5-Pydi                                                                             Cl                                                                              COOEt                            1042 Oc   H  Ac       TMB H                                                                                 ##STR561##                                                                        1 p-Phn  Cl                                                                              COOEt                            1043 Oc   H  Ac       TMB H                                                                                 ##STR562##                                                                        1 p-Phn  Cl                                                                              COOEt                            1044 Oc   H  Ac       TMB H                                                                                 ##STR563##                                                                        1 6-Me-1,3-Phn                                                                         Cl                                                                              COOEt                            1045 Oc   H  Ac       TMB H                                                                                 ##STR564##                                                                        1 6-Me-1,3-Phn                                                                         Cl                                                                              COOEt                            1046 Oc   H  Ac       TMB H                                                                                 ##STR565##                                                                        1 2,5-Pydi                                                                             Cl                                                                              COOEt                            1047 Oc   H  Ac       TMB H                                                                                 ##STR566##                                                                        1 2,5-Pydi                                                                             Cl                                                                              COOEt                            1048 5,5-DMH                                                                            Me Ac       Me  Me                                                                                ##STR567##                                                                        1 p-Phn  Cl                                                                              COOEt                            1049 Bz    .sub.- iPr                                                                      H         .sub.- iPr                                                                       H                                                                                 ##STR568##                                                                        1 p-Phn  Cl                                                                              COOEt                            1050 Nn   Me H        Me  H                                                                                 ##STR569##                                                                        1 p-Phn  Cl                                                                              COOEt                            1051 Dc   Me Ac       MeO MeO                                                                               ##STR570##                                                                        1 p-Phn  Cl                                                                              COOEt                            1052 3,7-DMO                                                                            Me H        Me  Me                                                                                ##STR571##                                                                        1 p-Phn  Cl                                                                              COOEt                            1053 3,7-DMO                                                                            Me Ac       Me  Me                                                                                ##STR572##                                                                        1 p-Phn  Cl                                                                              COOEt                            1054 3,7-DMO                                                                            Me Ac       Me  Me                                                                                ##STR573##                                                                        1 p-Phn  Cl                                                                              COOEt                            1055 3,7-DMO                                                                            Me Ac       Me  Me                                                                                ##STR574##                                                                        1 6-Me-1,3-Phn                                                                         Cl                                                                              COOEt                            1056 3,7-DMO                                                                            Me Ac       Me  Me                                                                                ##STR575##                                                                        1 6-Me-1,3-Phn                                                                         Cl                                                                              COOEt                            1057 3,7-DMO                                                                            Me Ac       Me  Me                                                                                ##STR576##                                                                        1 2,5-Pydi                                                                             Cl                                                                              COOEt                            1058 3,7-DMO                                                                            Me Ac       Me  Me                                                                                ##STR577##                                                                        1 2,5-Pydi                                                                             Cl                                                                              COOEt                            1059 3,7-DMO                                                                            H  H         .sub.- tBu                                                                       H                                                                                 ##STR578##                                                                        1 p-Phn  Cl                                                                              COOEt                            1060 3,7-DMO                                                                            H  Ac        .sub.- tBu                                                                       H                                                                                 ##STR579##                                                                        1 p-Phn  Cl                                                                              COOEt                            1061 3,7-DMO                                                                            H  H         .sub.- tBu                                                                       H                                                                                 ##STR580##                                                                        1 p-Phn  Cl                                                                              COOEt                            1062 3,7-DMO                                                                            H  Ac        .sub.- tBu                                                                       H                                                                                 ##STR581##                                                                        1 p-Phn  Cl                                                                              COOEt                            1063 3,7-DMO                                                                            H  H         .sub.- tBu                                                                       H                                                                                 ##STR582##                                                                        1 6-Me-1,3-Phn                                                                         Cl                                                                              COOEt                            1064 3,7-DMO                                                                            H  Ac        .sub.- tBu                                                                       H                                                                                 ##STR583##                                                                        1 6-Me-1,3-Phn                                                                         Cl                                                                              COOEt                            1065 3,7-DMO                                                                            H  H         .sub.- tBu                                                                       H                                                                                 ##STR584##                                                                        1 6-Me-1,3-Phn                                                                         Cl                                                                              COOEt                            1066 3,7-DMO                                                                            H  Ac        .sub.- tBu                                                                       H                                                                                 ##STR585##                                                                        1 6-Me-1,3-Phn                                                                         Cl                                                                              COOEt                            1067 3,7-DMO                                                                            H  Ac        .sub.- tBu                                                                       H                                                                                 ##STR586##                                                                        1 2,5-Pydi                                                                             Cl                                                                              COOEt                            1068 3,7-DMO                                                                            H  Ac        .sub.- tBu                                                                       H                                                                                 ##STR587##                                                                        1 2,5-Pydi                                                                             Cl                                                                              COOEt                            1069 3,7-DMO                                                                            H  Ac       TMB H                                                                                 ##STR588##                                                                        1 p-Phn  Cl                                                                              COOEt                            1070 3,7-DMO                                                                            H  Ac       TMB H                                                                                 ##STR589##                                                                        1 p-Phn  Cl                                                                              COOEt                            1071 3,7-DMO                                                                            H  Ac       TMB H                                                                                 ##STR590##                                                                        1 6-Me-1,3-Phn                                                                         Cl                                                                              COOEt                            1072 3,7-DMO                                                                            H  Ac       TMB H                                                                                 ##STR591##                                                                        1 6-Me-1,3-Phn                                                                         Cl                                                                              COOEt                            1073 3,7-DMO                                                                            H  AC       TMB H                                                                                 ##STR592##                                                                        1 2,5-Pydi                                                                             Cl                                                                              COOEt                            1074 3,7-DMO                                                                            H  Ac       TMB H                                                                                 ##STR593##                                                                        1 2,5-Pydi                                                                             Cl                                                                              COOEt                            1075 3,7-DMO                                                                            H  Boz      TMB H                                                                                 ##STR594##                                                                        1 p-Phn  Cl                                                                              COOEt                            1076 3,7-DMO                                                                            H  Ac       Me  H                                                                                 ##STR595##                                                                        1 p-Phn  Cl                                                                              COOH                             1077 7,7-DMO                                                                            Me H        Me  Me                                                                                ##STR596##                                                                        1 p-Phn  Cl                                                                              COOEt                            1078 7,7-DMO                                                                            Me Ac       Me  Me                                                                                ##STR597##                                                                        1 p-Phn  Cl                                                                              COOEt                            1079 7,7-DMO                                                                            Me H        Me  Me                                                                                ##STR598##                                                                        1 p-Phn  Cl                                                                              COOEt                            1080 7,7-DMO                                                                            Me Ac       Me  Me                                                                                ##STR599##                                                                        1 p-Phn  Cl                                                                              COOEt                            1081 7,7-DMO                                                                            Me Ac       Me  Me                                                                                ##STR600##                                                                        1 6-Me-1,3-Phn                                                                         Cl                                                                              COOEt                            1082 7,7-DMO                                                                            Me Ac       Me  H                                                                                 ##STR601##                                                                        1 6-Me-1,3-Phn                                                                         Cl                                                                              COOEt                            1083 7,7-DMO                                                                            Me Ac       Me  H                                                                                 ##STR602##                                                                        1 2,5-Pydi                                                                             Cl                                                                              COOEt                            1084 7,7-DMO                                                                            Me Ac       Me  H                                                                                 ##STR603##                                                                        1 2,5-Pydi                                                                             Cl                                                                              COOEt                            1085 7,7-DMO                                                                            H  Ac        .sub.- tBu                                                                       H                                                                                 ##STR604##                                                                        1 p-Phn  Cl                                                                              COOEt                            1086 7,7-DMO                                                                            H  Ac        .sub.- tBu                                                                       H                                                                                 ##STR605##                                                                        1 p-Phn  Cl                                                                              COOEt                            1087 7,7-DMO                                                                            H  Ac       TMB H                                                                                 ##STR606##                                                                        1 p-Phn  Cl                                                                              COOEt                            1088 Bz   Me H        Me  Me                                                                                ##STR607##                                                                        1 p-Phn  Cl                                                                              COOEt                            1089 Bz   Me Ac       Me  Me                                                                                ##STR608##                                                                        1 p-Phn  Cl                                                                              COOEt                            1090 Bz   Me H        Me  Me                                                                                ##STR609##                                                                        1 p-Phn  Cl                                                                              COOEt                            1091 Bz   Me Ac       Me  Me                                                                                ##STR610##                                                                        1 p-Phn  Cl                                                                              COOEt                            1092 Bz   H  H         .sub.- tBu                                                                       H                                                                                 ##STR611##                                                                        1 p-Phn  Cl                                                                              COOEt                            1093 Bz   H  H        TMB H                                                                                 ##STR612##                                                                        1 p-Phn  Cl                                                                              COOEt                            1094 Me   Me HOOCCH.sub.2                                                                           Me  Me                                                                                ##STR613##                                                                        1 p-Phn  Cl                                                                              COOEt                            1095 Me   Me EtOOCCH.sub.2                                                                          Me  Me                                                                                ##STR614##                                                                        1 p-Phn  Cl                                                                              COOEt                            1096 Me   H  HOOCCH.sub.2                                                                            .sub.- tBu                                                                       H                                                                                 ##STR615##                                                                        1 2,5-Pydi                                                                             Cl                                                                              COOH                             1097 3,7-DMO                                                                            H  HOOC(CH.sub.2).sub.2                                                                    .sub.- tBu                                                                       H                                                                                 ##STR616##                                                                        2 p-Phn  Br                                                                              COOH                             1098 Me   H  HOOCCMe.sub.2                                                                          TMB H                                                                                 ##STR617##                                                                        1 6-Me-1,3-Phn                                                                         Cl                                                                              COOPr                            __________________________________________________________________________

In addition, other compounds useful as intermediates are shown in Tables28 and 29, the abbreviations used again being as defined in relation toTables 1-26.

Compounds of formulae (XIII-28) and (XIII-29): ##STR618##

are as defined in Table 27 and 28, respectively:

                                      TABLE 28                                    __________________________________________________________________________    Cpd.                                                                          No.                                                                              L   U    R.sup.2                                                                          R.sup.3                                                                         R.sup.4                                                                           R.sup.5                                                                          n Ar     X A                                          __________________________________________________________________________    2001                                                                             OH  > CH.sub. 2                                                                        Me H Me  Me 1 p-Phn  Cl                                                                              COOH                                       2002                                                                             OH  > CH.sub. 2                                                                        Me Ac                                                                              Me  Me 1 p-Phn  Cl                                                                              COOEt                                      2003                                                                             OH  > CH.sub. 2                                                                        Me H Me  Me 2 p-Phn  Cl                                                                              COOH                                       2004                                                                             OH  > CH.sub. 2                                                                        Me H Me  Me 1 6-Me-1,3-Phn                                                                         Cl                                                                              COOMe                                      2005                                                                             OH  > CH.sub. 2                                                                        Me Ac                                                                              Me  Me 1 6-Me-1,3-Phn                                                                         Cl                                                                              COOEt                                      2006                                                                             OH  > CH.sub. 2                                                                        Me H Me  Me 1 2,5-Pydi                                                                             Cl                                                                              COOH                                       2007                                                                             OH  > CH.sub. 2                                                                        Me Ac                                                                              Me  Me 1 2,5-Pydi                                                                             Cl                                                                              COO .sub.-iPr                              2008                                                                             OH  > CH.sub. 2                                                                        H  H  .sub.-tBu                                                                        H  1 p-Phn  Cl                                                                              COOH                                       2009                                                                             OH  > CH.sub. 2                                                                        H  Ac                                                                               .sub.-tBu                                                                        H  1 p-Phn  Cl                                                                              COOEt                                      2010                                                                             OH  > CH.sub. 2                                                                        H  H  .sub.-tBu                                                                        H  1 6-Me-1,3-Phn                                                                         Cl                                                                              COOH                                       2011                                                                             OAc > CH.sub. 2                                                                        H  Ac                                                                               .sub.-tBu                                                                        H  1 6-Me-1,3-Phn                                                                         Cl                                                                              COO- .sub.-tBu                             2012                                                                             OH  > CH.sub. 2                                                                        H  H  .sub.-tBu                                                                        H  1 2,5-Pydi                                                                             Cl                                                                              COOH                                       2013                                                                             OH  > CH.sub. 2                                                                        H  Ac                                                                               .sub.-tBu                                                                        H  1 2,5-Pydi                                                                             Cl                                                                              COOPh                                      2014                                                                             OH  > CH.sub. 2                                                                        H  H TMB H  1 p-Phn  Cl                                                                              COOH                                       2015                                                                             OH  > CH.sub. 2                                                                        H  H TMB H  1 6-Me-1,3-Phn                                                                         Cl                                                                              COOH                                       2016                                                                             OH  > CH.sub. 2                                                                        H  H TMB H  1 2,5-Pydi                                                                             Cl                                                                              COOH                                       __________________________________________________________________________

                                      TABLE 29                                    __________________________________________________________________________    Cpd.                                                                          No.                                                                              R.sup.2                                                                          R.sup.3  R.sup.4                                                                           R.sup.5                                                                          n Ar     X A                                            __________________________________________________________________________    2017                                                                             Me H        Me  Me 1 p-Phn  Cl                                                                              --COOH                                       2018                                                                             Me Ac       Me  Me 1 p-Phn  Cl                                                                              --COOEt                                      2019                                                                             Me H        Me  Me 1 6-Me-1,3-Phn                                                                         Cl                                                                              --COOH                                       2020                                                                             Me Ac       Me  Me 1 6-Me-1,3-Phn                                                                         Cl                                                                              --COOMe                                      2021                                                                             Me H        Me  Me 1 2,5-Pydi                                                                             Cl                                                                              --COOH                                       2022                                                                             Me Ac       Me  Me 1 2,5-Pydi                                                                             Cl                                                                              --COOEt                                      2023                                                                             H  H         .sub.- tBu                                                                       H  1 p-Phn  Cl                                                                              --COOH                                       2024                                                                             H  H         .sub.- tBu                                                                       H  1 6-Me-1,3-Phn                                                                         Cl                                                                              --COOH                                       2025                                                                             H  H         .sub.- tBu                                                                       H  1 2,5-Pydi                                                                             Cl                                                                              --COOH                                       2026                                                                             H  H        TMB H  1 p-Phn  Cl                                                                              --COOH                                       2027                                                                             H  H        TMB H  1 p-Phn  Cl                                                                              --COO .sub.- iBu                             2028                                                                             Me HOOC--CH.sub.2 --                                                                      Me  Me 1 p-Phn  Cl                                                                              --COOH                                       2029                                                                             Me EtOOC--CH.sub.2 --                                                                     Me  Me 1 p-Phn  Cl                                                                              --COOEt                                      2030                                                                             Me EtOOC--CH.sub.2 --                                                                     Me  Me 1 2,5-Pydi                                                                             Cl                                                                              --COOEt                                      2031                                                                             H  HOOC--CH.sub.2 --                                                                       .sub.- tBu                                                                       H  1 p-Phn  Cl                                                                              --COOH                                       2032                                                                             H  EtOOC--CH.sub.2 --                                                                      .sub.- tBu                                                                       H  1 6-Me-1,3-Phn                                                                         Cl                                                                              --COOEt                                      2033                                                                             H  HOOC--CH.sub.2 --                                                                      TMB H  1 p-Phn  Cl                                                                              --COOH                                       2034                                                                             H  BuOOC--CH.sub.2 --                                                                     TMB H  1 p-Phn  Cl                                                                              COOBu                                        2035                                                                             H  HOOC--CH.sub.2 --                                                                      TMB H  1 p-Phn  Br                                                                              --COOH                                       2036                                                                             Me HOOCCMe.sub.2 --                                                                       Me  Me 1 p-Phn  Cl                                                                              --COOH                                       2037                                                                             H  HOOCCMe.sub.2 --                                                                        .sub.- tBu                                                                       H  1 p-Phn  Cl                                                                              --COOH                                       2038                                                                             H  HOOCCMe.sub.2 --                                                                       TMB H  1 p-Phn  Cl                                                                              --COOH                                       2039                                                                             H  EtOOCCMe.sub.2 --                                                                      Me  H  1 p-Phn  Cl                                                                              --COOEt                                      __________________________________________________________________________

The compounds of the invention have shown a very strong ability toinhibit the oxidation of unsaturated fatty acids and their esters (suchas linolic acid and ethyl linolate) and, accordingly, it is expectedthat these compounds will be able to prevent the oxidation ofphospholipids containing a high content of unsaturated fatty acids fromoxidation, even in vivo.

The compounds of the invention have been shown to have a very strongability to lower the level of lipid peroxides, as demonstrated, interalia, by the test against rat liver microsomal lipid peroxidationdescribed in Biochem. Biphys. Res. Commun., 95, 734 (1980). In addition,in experiments using alloxan-induced hyperlipaemic ice, the compoundshave demonstrated the ability to lower blood lipid peroxide,triglyceride and cholesterol levels. The compounds have also shown theability to lower blood sugar levels in a test using genetically diabeticmice of the KK strain. Moreover, the compounds of the invention are lesstoxic than many known compounds to experimental animals such as rats ormice and result in little anorexia, inhibition of body weight increaseand liver hypertrophy.

Accordingly, it is considered that the compounds of the presentinvention will be useful for the therapeutic treatment of humanhyperlipaemia, diabetes and complications thereof, especially diabetesmellitus. The compounds of the invention may be administered orally, forexample in the form of tablets, capsules, powders or granules, orparenterally, for example by injection or in the form of a suppository.The recommended dosage will, of course, vary depending upon the age andbody weight of the patient as well as the nature and severity of thedisease. However, for an adult human patient, a daily dose of from 50 mgto 5 g (which may be administered in a single dose or in divided doses)is recommended in the treatment of hyperlipaemia, diabetes mellitus andcomplications thereof.

The following Examples illustrate the preparation of various of thecompounds of the present invention. Preparation of various of thestarting materials employed in the Examples is illustrated in thesubsequent Preparations. The subsequent Test Examples illustrate thevaluable biological properties of these compounds.

In the nuclear magnetic resonance spectra reported in the Examples andPreparations, the abbreviation "nd" means that precise identification ofthe signal was not possible because of overlap by other signals or theabsorption of the solvent.

EXAMPLE 159]4-(6-Hydroxy-2-isobutyl-5,7,8-trimethyl-4-oxochroman-2-ylmethoxy)benzyl]thiazolidine-2,4-dione (Step D4)

A mixture of 0.5 g of ethyl3-[4-(6-acetoxy-2-isobutyl-5,7,8-trimethyl-4-oxochroman-2-ylmethoxy)phenyl]-2-chloropropionate(prepared as described in Preparation 9), 0.2 g of thiourea and 0.8 g ofsulfolane was heated at 120°-135° C. for 4 hours under a nitrogenstream. A mixture of 1 ml of concentrated hydrochloric acid, 1 ml ofwater and 5 ml of ethylene glycol monomethyl ether was then added to thereaction mixture, and the mixture was heated under reflux for 6 hours.The reaction mixture was then poured into water and extracted with ethylacetate. The ethyl acetate extract was dried over anhydrous sodiumsulfate. The solvent was distilled off and the residue was purified bypreparative silica gel thin layer chromatography using a 1:1 by volumemixture of hexane and ethyl acetate as developing solvent, to give thetitle compound, softening at 70°-78° C.

Nuclear Magnetic Resonance Spectrum (CDCl₃) δ ppm:

0.97 (6H, doublet, J+6 Hz);

1.5-2.1 (3H, nd);

2.12 (3H, singlet);

2.21 (3H, singlet);

2.53 (3H, singlet);

2.77 δ 2.99 (2H, AB type, J=16 Hz);

2.8-3.2 (1H, nd);

3.41 (1H, doublet of doublets, J=4 δ 14 Hz);

4.06 (2H, AB type, J=10 Hz);

4.43 (1H, doublet of doublets, j=4 δ 9 Hz);

4.6-5.3 (1H, broad singlet, disappeared on adding heavy water);

6.81 (2H, doublet, J=9 Hz);

7.12 (2H, doublet, J=9 Hz);

8.7-9.3 (1H, broad singlet, disappeared on adding heavy water).

EXAMPLE 25-[4-(6-Acetoxy-5,7,8-trimethyl-2-octylchroman-2-yl-methoxy)benzyl]thiazolidine-2,4-dione

A mixture of 2.1 g of ethyl3-[4-(6-acetoxy-5,7,8-trimethyl-2-octylchroman-2-ylmethoxy)phenyl]-2-chloropropionate(prepared as described in Preparation 18), 0.35 g of thiourea and 2.5 mlof sulfolane was heated for 7 hours at 120°-130° C. under a nitrogenatmosphere. The reaction mixture was then dissolved in benzene. Thebenzene solution was washed with water and dried over anhydrous sodiumsulfate. The solvent was distilled off under reduced pressure. Theresidue was purified by silica gel column chromatography, eluted with a10:1 by volume mixture of benzene and ethyl acetate, to give the titlecompound as a slightly yellow, foamy solid.

Rf value on silica gel thin layer chromatography=0.55 (developingsolvent, benzene:ethyl acetate=4:1 by volume).

Nuclear Magnetic Resonance Spectrum (CDCl₃) δ ppm:

0.7-1.0 (3H, multiplet);

1.1-2.0 (16H, multiplet);

1.97 (3H, singlet);

2.03 (3H, singlet);

2.08 (3H, singlet);

2.31 (3H, singlet);

2.60 (2H, broad triplet, J=6 Hz);

3.03 (1H, doublet of doublets, J=10 δ 15 Hz);

3.44 (1H, doublet of doublets, J=3 δ 15 Hz);

3.92 (2H, singlet);

4.45 (1H, doublet of doublets, J=3 δ 10 Hz);

6.85 (2H, doublet, J=9 Hz);

7.13 (2H, doublet, J=9 Hz);

8.0-8.9 (1H, broad, disappeared on adding heavy water).

EXAMPLE 35-[4-(6-Hydroxy-5,7,8-trimethyl-2-octylchroman-2-yl-methoxy)benzyl]thiazolidine-2,4-dione

A mixture of 2.1 g of ethyl3-[4-(6-acetoxy-5,7,8-trimethyl-2-octylchroman-2-ylmethoxy)phenyl]-2-chloropropionate(prepared as described in Preparation 18). 0.35 g of thiourea and 2.5 mlof sulfolane was heated for 7 hours at 120°-130° C. under a nitrogenatmosphere. A mixture of 3.6 ml of 2N aqueous hydrochloric acid and 5 mlof ethylene glycol monomethyl ether was then added to the reactionmixture, after which it was heated for a further 5 hours at 85°-90° C.The reaction mixture was then poured into water and extracted withbenzene. The benzene extract was washed with water and dried overanhydrous sodium sulfate. The solvent was distilled off under reducedpressure and the residue was purified by silica gel columnchromatography, using a 10:1 by volume mixture of benzene and ethylacetate as eluent, to give the title compound as a slightly yellow,foamy solid.

Rf value on silica gel thin layer chromatography=0.43 (trailing)(developing solvent, benzene:ethyl acetate=4:1 by volume).

Nuclear Magnetic Resonance Spectrum (CDCl₃) δ ppm:

0.7-1.0 (3H, multiplet);

1.1-2.1 (16H, multiplet);

2.10 (6H, singlet);

2.15 (3H, singlet);

2.61 (2H, broad triplet, J=6 Hz);

3.05 (1H, doublet of doublets, J=10 δ 15 Hz);

3.42 (1H, doublet of doublets, J=3 δ 15 Hz);

3.92 (2H, singlet);

4.22 (1H, singlet, disappeared on adding heavy water);

4.47 (1H, doublet of doublets, J=3 δ 10 Hz);

6.85 (2H, doublet, J=9 Hz);

7.13 (2H, doublet, J=9 Hz);

8.33 (1H, broad singlet, disappeared on adding heavy water).

EXAMPLE 45-[4-(6-Acetoxy-2-methyl-7-(1,1,3,3-tetramethylbutyl)-chroman-2-ylmethoxy)benzyl]thiazolidine-2,4dione

The procedure described in Example 2 was repeated, but using 7.0 g ofethyl3-{4-[6-acetoxy-2-methyl-7-(1,1,3,3-tetramethylbutyl)chroman-2-ylmethoxy]phenyl}-2-chloropropionate(prepared as described in Preparation 23), 1.2 g of thiourea and 9 ml ofsulfolane, to give the title compound as slightly yellow glassy solid,softening at 75°-80° C.

Nuclear Magnetic Resonance Spectrum (CDCl₃) δ ppm:

0.79 (9H, singlet);

1.36 (6H, singlet);

1.45 (3H, singlet);

1.66-2.28 (2H, nd);

1.80 (2H, singlet);

2.29 (3H, singlet);

2.73 (2H, broad triplet, J=6 Hz);

3.28 (1H, doublet of doublets, J=9 δ 14 Hz);

3.45 (1H, doublet of doublets, J=4 δ 14 Hz);

3.93 (2H, AB type, J=9 Hz);

4.49 (1H, doublet of doublets, J=4 δ 9 Hz);

6.75 (1H, singlet);

6.86 (1H, singlet);

6.90 (2H, doublet, J=9 Hz);

7.13 (2H, doublet, J=9 Hz);

8.1-8.7 (1H, broad, disappeared on adding heavy water).

EXAMPLE 55-{4-[6Hydroxy-2-methyl-7-(1,1,3,3-tetramethylbutyl)-chroman-2-ylmethoxy]benzyl}thiazolidine-2,4-dione

The procedure described in Example 3 was repeated, but using 7.0 g ofethyl3-{4-[6-acetoxy-2-methyl-7-(1,1,3,3-tetramethylbutyl)chroman-2-ylmethoxy]phenyl}-2-chloropropionate(prepared as described in Preparation 23), 1.2 g of thiourea, 9 ml ofsulfolane, 13 ml of 2N hydrochloric acid and 20 ml of ethylene glycolmonomethyl ether, to give the title compound as a slightly yellow glassysolid, softening at 80°-85° C.

Nuclear Magnetic Resonance Spectrum (CDCl₃) δ ppm:

0.78 (9H, singlet);

1.41 (9 H, singlet);

1.60-2.30 (2H, nd);

1.91 (2H, singlet);

2.67 (2H, broad triplet, J=6.5 Hz);

3.07 (1H, doublet of doublets, J=10 δ 14 Hz);

3.45 (1H, doublet of doublets, J=4 and 14 Hz);

3.93 (2H, AB type, J=9 Hz);

4.45 (1H, singlet, disappeared on adding heavy water);

4.49 (1H, doublet of doublets, J=4 δ 10 Hz);

6.34 (1H, singlet);

6.77 (1H, singlet);

6.88 (2H, doublet, J=9 Hz);

7.17 (2H, doublet, J=9 Hz);

8.4 (1H, broad singlet, disappeared on adding heavy water).

EXAMPLE 65-{4-[6-Acetoxy-2-methyl-4-oxo-7-(1,1,3,3-tetramethylbutyl)chroman-2-ylmethoxy]benzyl}thiazolidine-2,4-dione

The procedure described in Example 2 was repeated, but using 7.3 g ofethyl 3-{4-[6-acetoxy-2-methyl-4-oxo-7-(1,1,3,3-tetramethylbutyl)chroman-2-ylmethoxy]phenyl}-2-chloropropionate (prepared as described inPreparation 25), 1.3 g of thiourea and 8 ml of sulfolane, to give thetitle compound as a slightly yellow powder, softening at 80° -88° C.

Nuclear Magnetic Resonance Spectrum (CDCl₃) δ ppm:

0.78 (9H, singlet);

1.37 (6H, singlet);

1.53 (3H, singlet);

1.83 (2H, singlet);

2.30 (3H, singlet);

2.70 (1H, doublet, J=17 Hz);

2.8-3.2 (1H, nd);

3.10 (1H, doublet, J=17 Hz);

3.45 (1H, doublet of doublets, J=4 δ 15 Hz);

4.00 δ 4.12 (2H, AB type, J=9 Hz);

4.48 (1H, doublet of doublets, J=4 δ 9 Hz);

6.85 (2H, doublet, J=9 Hz);

7.02 (1H, singlet);

7.17 (2H, doublet, J=9 Hz);

7.51 (1H, singlet);

8.3-9.0 (1H, broad, disappeared on adding heavy water).

EXAMPLE 75-{4-[6-Hydroxy-2-methyl-4-oxo-7-(1,1,3,3-tetramethylbutyl)chroman-2-ylmethoxy]benzyl}thiazolidine-2,4-dione

A mixture of 5.2 g of5-{4-[6-acetoxy-2-methyl-4-oxo-7-(1,1,3,3-tetramethylbutyl)chroman-2-ylmethoxy]-benzyl}-2-iminothiazolidin-4-one prepared asdescribed in Preparation 26), 16 ml of 2N hydrochloric acid and 25 ml ofethylene glycol monomethyl ether was heated for 6 hours at 85°-90° C.under a nitrogen atmosphere. The reaction mixture was then poured intowater and extracted with benzene. The benzene extract was washed withwater and dried over anhydrous sodium sulfate. The solvent was distilledoff under reduced pressure and the residue was purified by silica gelcolumn chromatography, eluted with a 4:1 by volume mixture of benzeneand ethyl acetate, to give the title compound as a slightly yellow foamysolid, softening at 100°-105° C.

Nuclear Magnetic Resonance Spectrum (CDCl₃) δ ppm:

0.77 (9H, singlet);

1.43 (6H, singlet);

1.52 (3H, singlet);

2.00 (2H, singlet);

2.70 (1H, doublet, J=17 Hz);

2.8-3.2 (1H, nd);

3.12 (1H, doublet, J=17 Hz);

3.43 (1H, doublet of doublets, J=4 δ 15 Hz);

4.00 δ 4.10 (2H, AB type, J=9 Hz);

4.49 (1H, doublet of doublets, J=4 δ 9 Hz);

6.1 (1H, broad singlet, disappeared on adding heavy water);

6.85 (2H, doublet, J=9 Hz);

6.93 (1H, singlet);

7.15 (2H, doublet, J=9 Hz);

7.30 (1H, singlet);

8.2-9.3 (1H, broad, disappeared on adding heavy water).

EXAMPLE 85-{4-[2-(3,7-Dimethyloctyl)-6-hydroxy-5,7,8-trimethyl-4-oxochroman-2-ylmethoxy]benzyl}thiazolidine-2,4-dione

The procedure described in Example 3 was repeated, but using 1.1 g ofethyl3-{4-[6-acetoxy-2-(3,7-dimethyloctyl)-5,7,8-trimethyl-4-oxochroman-2-ylmethoxy]phenyl}-2-chloropropionate(prepared as described in Preparation 33), 0.2 g of thiourea, 1.5 ml ofsulfolane, 5 ml of 2N aqueous hydrochloric acid and 10 ml of ethyleneglycol monomethyl ether, to give the title compound, as a slightlyyellow powder, softening at 41°-45° C.

Nuclear Magnetic Resonance Spectrum (CDCl₃) δ ppm:

0.85 (9H, doublet, J=7 Hz);

1.0-2.0 (12H, multiplet);

2.13 (3H, singlet);

2.22 (3H, singlet);

2.55 (3H, singlet);

2.65-3.2 (3H, multiplet);

3.43 (1H, doublet of doublets, J=4 δ -Hz);

4.05 (2H, singlet);

4.35-5.3 (1H, broad, disappeared on adding heavy water);

4.46 (1H, doublet of doublets, J=4 δ 10 Hz);

6.83 (2H, doublet, J=9 Hz);

7.15 (2H, doublet, J=9 Hz);

8.0-9.5 (1H, broad, disappeared on adding heavy water).

EXAMPLE 95-[2-(6-Hydroxy-2,5,7,8-tetramethylchroman-2-ylmethoxy)pyridin-5-ylmethyl]thiazolidine-2,4-dione

The procedure described in Example 3 was repeated, but using 3.8 g ofethyl3-[2-(6-acetoxy-2,5,7,8-tetramethylchroman-2-ylmethoxy)pyridin-5-yl]-2-chloropropionate(prepared as described in Preparation 38), 0.77 g of thiourea, 5.0 ml ofsulfolane, 4.5 ml of ethylene glycol monomethyl ether, 1.5 ml ofconcentrated hydrochloric acid and 4.5 ml of water, to give the titlecompound, softening at 87°-94° C.

Nuclear Magnetic Resonance Spectrum (CDCl₃) δ ppm:

1.38 (3H, singlet);

1.7-2.3 (2H, multiplet);

2.06 (3H, singlet);

2.09 (3H, singlet);

2.14 (3H, singlet);

2.63 (2H, broad triplet, J=6 Hz);

3.10 (1H, doublet of doublets, J=15 δ 7.5 Hz);

3.33 (1H, doublet of doublets, J=15 δ 4.5 Hz);

4.0-5.0 (1H, broad, disappeared on adding heavy water);

4.32 (3H, singlet);

4.47 (1H, doublet of doublets, J=7.5 δ 4.5 Hz);

6.75 (1H, doublet, J=9 Hz);

7.46 (1H, doublet of doublets, J=9 δ 3 Hz);

8.02 (1H, doublet, J=3 Hz).

EXAMPLE 105-[3-(7-t-Butyl-6-hydroxy-2-methyl-4-oxochroman-2-ylmethoxy)-4-methylbenzyl]thiazolidine-2,4-dione

the procedure described in Example 3 was repeated, but using 2,4 g ofethyl 3-[3-(6-acetoxy-7-t-butyl-2-methyl-4-oxochroman-2-ylmethoxy)-4-methylphenyl]-2-chloropropionate (prepared as described inPreparation 42), 0.7 g of thiourea, 5 ml of sulfolane, 10 ml of 2Naqueous hydrochloric acid and 15 ml of ethylene glycol monomethyl ether,to give the title compound.

Rf value on silica gel thin layer chromatography=0.44 (developingsolvent, benzene:ethyl acetate=1:1 by volume).

Nuclear Magnetic Resonance Spectrum (CDCl₃) δ ppm:

1.40 (9H, singlet);

1.57 (3H, singlet);

2.14 (3H, singlet;

2.77 (1H, doublet, J=16 Hz);

3.01 (1H, doublet of doublets, J=10 δ 14 Hz);

3.07 (1H, doublet, J=16 Hz);

3.44 (1H, doublet of doublets, J=4 δ 14 Hz);

3.99 δ 4.13 (2H, AB type, J=10 Hz);

4.50 (1H, doublet of doublets, J=4 δ 10 Hz);

5.84 (1H, broad singlet, disappeared on adding heavy water);

6.6-6.85 (2H, nd);

6.91 (1H, singlet);

7.08 (1H, doublet, J=7.5 Hz);

7.32 (1H, singlet);

8.3-9.0 (1H, broad, disappeared on adding heavy water).

EXAMPLE 115-[4-(6-Hydroxy-5,7,8-trimethyl-4-oxochroman-2-ylmethoxy)benzyl]thiazolidine-2,4-dione

The procedure described in Example 3 was repeated, but using 2.2 g ofethyl3-[4-(6-acetoxy-2-hydroxy-5,7,8-trimethyl-4-oxochroman-2-ylmethoxy)phenyl]-2-chloropropionate (prepared as described in Preparation 45),0.8 g of thiourea, 4.5 g of sulfolane, 70 ml of ethylene glycolmonomethyl ether, 8 ml of water and 4 ml of 35% w/v aqueous hydrochloricacid, to give the title compound, melting at 249°-252° C.

Nuclear Magnetic Resonance Spectrum [(CD₃)₂ SO] δppm:

2.25 (6H, singlet);

2.63 (3H, singlet);

2.7-3.8 (2H, nd);

4.88 (1H, doublet of doublets, J=4 δ 9 Hz);

5.11 (2H, singlet);

6.28 (1H, singlet);

7.05 (2H, doublet, J=9 Hz);

7.24 (2H, doublet, J=9 Hz);

8.3-8.7 (1H, broad singlet, disappeared on adding heavy water).

EXAMPLE 125-[4-(6-Hydroxy-2,5,7,8-tetramethylchroman-2-ylmethoxy)benzyl]-5-methylthiazolidine-2,4-dione

The procedure described in Example 3 was repeated, but using 1.17 g ofethyl3-[4-(6-acetoxy-2,5,7,8-tetramethylchroman-2-ylmethoxy)phenyl]-2-chloro-2-methylpropionate (prepared as described in Preparation 46), 0.63 g ofthiourea, 3 g of sulfolane, 10 ml of ethylene glycol monomethyl ether, 3ml of water and 2 ml of 35% w/v aqueous hydrochloric acid, to give thetitle compound, softening at 69°-72° C.

Nuclear Magnetic Resonance Spectrum (CDCl₃) δ ppm:

1.40 (3H, singlet);

1.72 (3H, singlet);

1.6-2.3 (2H, nd);

2.10 (6H, singlet);

2.16 (3H, singlet);

2.62 (2H, broad triplet, J=7 Hz);

2.94 (1H, doublet, J=14 Hz);

3.24 (1H, doublet, J=14 Hz);

3.84 and 3.97 (2H, AB type, J=9 Hz);

4.40 (1H, broad singlet, disappeared on adding heavy water);

6.84 (2H, doublet, J=9 Hz);

7.13 (2H, doublet, J=9 Hz);

8.4-8.9 (1H, broad singlet, disappeared on adding heavy water).

EXAMPLE 135-{4-[6-Hydroxy-4-(E)-hydroxyimino-2,5,7,8-tetramethylchroman-2-ylmethoxy]benzyl}thiazolidine-2,4-dione

A mixture of 5 g of5-[4-(6hydroxy-2,5,7,8-tetramethyl-4-oxochroman-2-ylmethoxy)benzyl]thiazolidine-2,4-dione(prepared as described in Example 22 of copending U.S. Ser. No.644,996), 3 g of hydroxylamine hydrochloride, 50 g of methanol and 3 gof pyridine was stirred for 1 week at room temperature. At the end ofthis time, ethyl acetate and an aqueous solution of potassium carbonatewere added. The organic layer was separated and dried over anhydroussodium sulfate. The solvent was distilled off and the residue waspurified by silica gel column chromatography, eluted with a 1:1 byvolume mixture of hexane and ethyl acetate, to give the title compound,softening at 84°-100° C.

Nuclear Magnetic Resonance Spectrum [(CD₃)₂ CO] δppm:

1.42 (3H, singlet);

2.09 (3H, singlet);

2.18 (3H, singlet);

2.48 (3H, singlet);

3.03 (1H, doublet of doublets, J=9 δ 14 Hz);

3.07 (2H, singlet);

3.43 (1H, doublet of doublets, J=4 δ 14 Hz);

4.05 (2H, singlet);

4.72 (1H, doublet of doublets, J=4 δ 9 Hz);

6.92 (2H, doublet, J=9 Hz);

7.21 (2H, doublet, J=9 Hz);

9.7-10.5 (1H, broad singlet, disappeared on adding heavy water).

EXAMPLE 145-{4-[6-Hydroxy-4-(Z)-hydroxylimino-2,5,7,8-tetramethylchroman-2-ylmethoxy]benzyl}thiazolidine-2,4-dione

The title compound, softening at 100°-105° C., was obtained from thefraction that was eluted following the reaction containing the compoundof Example 13 in the column chromatography conducted in Example 13 andusing the same eluent.

Nuclear Magnetic Resonance Spectrum [(CD₃)₂ CO]δ ppm:

1.46 (3H, singlet);

2.04 (3H, singlet);

2.18 (6H, singlet);

2.58 (1H, doublet, J=13 Hz);

2.87 (1H, doublet, J=13 Hz);

3.10 (1H, doublet of doublets, J=9 δ 14 Hz);

3.43 (1H, doublet of doublets, J=4 δ 14 Hz);

4.01 (2H, singlet);

4.74 (1H, doublet of doublets, J=4 δ 9 Hz);

6.92 (2H, doublet, J=9 Hz);

7.22 (2H, doublet, J=9 Hz);

9.4-10.6 (1H, broad singlet, disappeared on adding heavy water).

EXAMPLE 155-{4-[6-Hydroxy-4-(Z)-hydroxyimino-2,5,7,8-tetramethylchroman-2-ylmethoxy]benzyl}thiazolidine-2,4-dione

27 mg of59{4-[6-hydroxy-4-(E)-hydroxyimino-2,5,7,8-tetramethylchroman-2-ylmethoxy]-benzyl}thiazolidine-2,4-dione (prepared as described in Example 13) was heatedon an oil bath for 5 hours at 140°÷5° C. The reaction mixture was thensubjected to high pressure liquid chromatography, which confirmed thepresence of the title compound (the same compound as in Example 14).

EXAMPLE 165-{4-[6Hydroxy-4-(E)-hydroxyimino-2,5,7,8-tetramethylchroman-2-ylmethoxy]benzyl}thiazolidine-2,4-dione

62 mg of5-{4-[6-hydroxy-4-(Z)-hydroxyimino-2,5,7,8-tetramethylchroman-2-ylmethoxy]benzyl}-thiazolidine-2,4-dione (prepared as described in Example 14) wereheated in an oil bath for 5 hours at 140°±5° C. The reaction mixture wassubjected to high pressure liquid chromatography, to confirm thepresence of the title compound (the same compound as described inExample 13).

EXAMPLE 175-{4-[6-Acetoxy-4-(E)-acetoxyimino-2,5,7,8-tetramethylchroman-2-ylmethoxy]benzyl}thiazolidine-2,4-dione

A mixture of 1 g of5-{4-[6-hydroxy-4-(E)-hydroxyimino-2,5,7,8tetramethylchroman-2-ylmethoxy]benzyl}thiazolidine-2,4-dione (prepared as described in Example 13),1.3 g of acetic anhydride and 10 ml of pyridine was allowed to stand for8 days at room temperature, after which it was heated for 8 hours at60°-80° C. An aqueous solution of potassium carbonate and ethyl acetatewere then added to the reaction mixture. The organic layer was separatedand dried over anhydrous sodium sulfate. The solvent was distilled offand the residue was purified by silica gel column chromatography, elutedwith a 4:1 by volume mixture of hexane and ethyl acetate, to give thetitle compound, softening at 93°-97° C.

Nuclear Magnetic Resonance Spectrum (CDCl₃) δ ppm:

1.48 (3H, singlet);

2.07 (3H, singlet);

2.10 (3H, singlet);

2.22 (3H, singlet);

2.33 (3H, singlet);

2.42 (3H, singlet);

3.00 (1H, doublet, J=17 Hz);

3.26 (1H, doublet, J=17 Hz);

3.0-3.3 (1H, nd);

3.41 (1H, doublet of doublets, J=4 δ 14 Hz);

3.91 and 4.06 (2H, AB type, J=9 Hz);

4.47 (1H, doublet of doublets, J=4 δ 9 Hz);

6.84 (2H, doublet, J=9 Hz);

7.14 (2H, doublet, J=9 Hz).

EXAMPLE 185-{4-[6-Benzoyloxy-4-(E)-benzoyloxyimino-2,5,7,8tetramethylchroman-2-ylmethoxy]benzyl}thiazolidine-2,4-dione

A mixture of 1 g of5-{4-[6-hydroxy-4-(E)-hydroxyimino-2,5,7,8tetramethylchroman-2-ylmethoxy]benzyl}-thiazolidine-2,4-dione (prepared as described in Example 13),1.7 g of benzoyl bromide, 10 ml of pyridine and 5 ml ofdimethylformamide was allowed to stand for 6 days at room temperature,after which it was heated for 8 hours at 60°-80° C. An aqueous solutionof potassium carbonate and ethyl acetate were then added to the reactionmixture. The organic layer was separated and dried over anhydrous sodiumsulfate. The solvent was distilled off and the residue was purified bysilica gel column chromatography eluted with a 4:3 by volume mixture ofhexane and ethyl acetate, to give the title compound, softening at101°-107° C.

Nuclear Magnetic Resonance Spectrum (CDCl₃) δ ppm:

1.55 (3H, singlet);

2.14 (6H, singlet);

2.58 (3H, singlet);

2.8-3.7 (4H, nd);

3.98 and 4.12 (2H, AB type, J=9 Hz);

4.45 (1H, doublet of doublets, J=4 δ 9 Hz);

6.84 (2H, doublet, J=9 Hz);

7.14 (2H, doublet, J=9 Hz);

7.3-7.8 (6H, multiplet);

7.9-8.5 (4H, multiplet).

EXAMPLE 195-{4-[2,5,7,8-Tetramethyl-6-nicotinoyloxy-4-(E)-nicotinoyloxyiminochroman-2-ylmethoxy]benzyl}-thiazolidine-2,4-dione

A mixture of 1 g of5-{4-[6-hydroxy-4-(E)-hydroxyimino-2,5,7,8-tetramethylchroman-2-ylmethoxy]benzyl}thiazolidine-2,4-dione (prepared as described in Example 13),1.1 g of nicotinoyl chloride hydrochloride, 12 ml of pyridine and 12 mlof dimethylformamide was allowed to stand for 6 days at roomtemperature, after which it was heated for 8 hours at 60°-80° C. Anaqueous solution of potassium carbonate and ethyl acetate were added tothe reaction mixture. The organic layer was separated and dried overanhydrous sodium sulfate. The solvent was distilled off, and the residuewas purified by silica gel column chromatography eluted with a 2:3 byvolume mixture of hexane and ethyl acetate, followed by preparative thinlayer silica gel chromatography (developing solvent, hexane:ethylacetate=1.10 by volume), to give the title compound, softening at123°-130° C.

Nuclear Magnetic Resonance Spectrum (CDCl₃) δ ppm:

1.56 (3H, singlet);

2.13 (3H, singlet);

2.17 (3H, singlet);

2.57 (3H, singlet);

2.8-3.7 (4H, nd);

3.99 and 4.16 (2H, AB type, J=9 Hz);

4.45 (1H, doublet of doublets, J=4 δ 9 Hz);

6.84 (2H, doublet, J=9 Hz);

7.15 (2H, doublet, J=9 Hz);

7.4-7.7 (2H, multiplet);

8.3-8.7 (2H, multiplet);

8.7-9.0 (2H, multiplet);

9.2-9.6 (2H, multiplet);

10.0-11.0 (1H, broad, disappeared on adding heavy water).

EXAMPLE 205-{4-[7-t-Butyl-6hydroxy-4-(E)-hydroxyimino-2methylchroman-2-ylmethoxy]benzyl}thiazolidine-2,4-dione

The procedure described in Example 13 was repeated, but using 1.32 g of5-[4-(7-t-butyl-6-hydroxy-2-methyl-4-oxochroman-2-ylmethoxy)benzyl]thiazolidine-2,4-dione(prepared as described in Example 24 of copending U.S. Ser. No.644,996), 2.0 g of hydroxylamine hydrochloride, 0.5 ml of pyridine and20 ml of methanol, to give the title compound as colorless crystals,melting at 235°-237° C. (with decomposition).

Nuclear Magnetic Resonance Spectrum [(CD₃)₂ CO]δ ppm:

1.40 (12H, singlet);

2.6-4.0 (1H, broad, disappeared on adding heavy water);

2.98 (2H, singlet);

3.10 (1H, doublet of doublets, J=9 δ 14 Hz);

3.43 (1H, doublet of doublets, J=4 δ 14 Hz);

4.05 (2H, singlet);

4.74 (1H, doublet of doublets, J=4 δ 9 Hz);

6.73 (1H, singlet);

6.95 (2H, doublet, J=9 Hz);

7.2-8.5 (1H, broad, disappeared on adding heavy water);

7.25 (2H, doublet, J=9 Hz);

7.30 (1H, singlet);

9.7-10.6 (1H, broad, disappeared on adding heavy water).

EXAMPLE 215-{4-[6-Hydroxy-4-(E)-hydroxyimino-2-methyl-7-(1,1,3,3-tetramethylbutyl)chroman-2-ylmethoxy]benzyl)thiazolidine-2,4-dione

The procedure described in Example 13 was repeated, but using 1.0 g of5-{4-[6-hydroxy-2-methyl-4-oxo-7-(1,1,3,3-tetramethylbutyl)chroman-2-ylmethoxy]benzyl}thiazolidine-2,4-dione (prepared as described inExample 7), 0.26 g of hydroxylamine hydrochloride, 0.3 g of pyridine and10 ml of methanol, to give the title compound as a white powder,softening at 115°-120° C.

Nuclear Magnetic Resonance spectrum [(CD₃)₂ CO] δppm:

0.76 (9H, singlet);

1.40 (9H, singlet);

2.00 (2H, singlet);

2.5-3.6 (1H, broad, disappeared on adding heavy water);

2.98 (2H, singlet);

3.09 (1H, doublet of doublets, J=9 δ 15 Hz);

3.44 (1H, doublet of doublets, J=4 δ 15 Hz);

4.03 (2H, singlet);

4.76 (1H, doublet of doublets, J=4 δ 0 Hz);

6.75 (1H, singlet);

6.93 (2H, doublet, J=9 Hz);

7.22 (2H, doublet, J=9 Hz);

7.25 (1H, singlet);

7.5-8.4 (1H, broad, disappeared on adding heavy water).

EXAMPLE 225-{4-[6-Hydroxy-4-(E)-hydroxyimino-2-isobutyl-5,7,8-trimethylchroman-b2-ylmethoxy]benzyl}thiazolidine-2,4-dione

The procedure described in Example 13 was repeated, but using 155 mg of5-[4-(6-hydroxy-2-isobutyl-5,7,8-trimethyl-4-oxochroman-2-ylmethoxy)benzyl]thiazolidine-2,4-dione (prepared as described in Example 1), 600mg of hydroxylamine hydrochloride, 4 ml of ethanol and 6 ml of pyridine,to give the title compound, softening at 77°-80° C.

Nuclear Magnetic Resonance Spectrum [(CD₃)₂ CO] δppm:

0.97 (6H, doublet, J=6 Hz);

1.6-2.3 (1H, nd);

1.78 (2H, doublet, J=6 Hz);

2.11 (3H, singlet);

2.18 (3H, singlet);

2.46 (3H, singlet);

2.7-3.7 (1H, broad, disappeared on adding heavy water);

2.8-3.2 (1H, nd);

3.09 (2H, singlet);

3.43 (1H, doublet of doublets, J=4 δ 14 Hz);

4.05 (2H, AB type, J=10 Hz);

4.72 (1H, doublet of doublets, J=4 δ 9 Hz);

6.91 (2H, doublet, J=9 Hz);

7.22 (2H, doublet, J=9 Hz);

9.8-10.5 (1H, broad singlet, disappeared on adding heavy water).

EXAMPLE 235-{4-[2-(3,7-Dimethyloctyl)-6-hydroxy-4-(E)-hydroxyimino-5,7,8-trimethylchroman-2-trimethylchroman-2ylmethoxy]benzyl}thiazolidine-2,4-dione

The procedure described in Example 13 was repeated, but using 150 mg of5-{4-[2-(3,7-dimethyloctyl)-6-hydroxy-5,7,8-trimethyl-4-oxochroman-2-ylmethoxy]benzyl}thiazolidine-2,4-dione (prepared as described inExample 8), 36 mg of hydroxylamine hydrochloride, 41 mg of pyridine and2 ml of methanol, to give the title compound as a slightly yellowpowder, softening at 55°-60 ° C.

Nuclear Magnetic Resonance Spectrum (CDCl₃) δ ppm:

0.83 (9H, doublet, J=7 Hz);

1.0-2.0 (12H, multiplet);

2.10 (3H, singlet);

2.18 (3H, singlet);

2.41 (3H, singlet);

2.9-3.2 (1H, nd);

2.92 (1H, doublet, J=17 Hz);

3.2-3.55 (1H, nd);

3.23 (1H, doublet, J=17 Hz);

3.94 (2H, singlet);

4.3-4.8 (1H, nd);

4.46 (1H, doublet of doublets, J=4 δ 10 Hz);

6.83 (2H, doublet, J=9 Hz);

7.15 (2H, doublet, J=9 Hz);

7.8-8.9 (2H, broad, disappeared on adding heavy water).

EXAMPLE 245-[4-(6-Hydroxy-2,5,7,8-tetramethyl-4-(E)-methoxyiminochroman-2-ylmethoxy)benzyl]thiazolidine-2,4dione

A mixture of 1 g of5-[4-(6-hydroxy-2,5,7,8-tetramethyl-4-oxochroman-2-ylmethoxy)benzyl]thiazolidine-2,4-dione(prepared as described in Example 22 of copending U.S. Ser. No.644,996), 0.6 g of methoxyamine hydrochloride and 5 g of methanol wasallowed to stand for 10 days at room temperature. At the end of thistime, ethyl acetate and an aqueous solution of potassium carbonate wereadded. The organic layer was separated and dried over anhydrous sodiumsulfate. The solvent was distilled off and the residue was purified bysilica gel column chromatography eluted with a 3:1 by volume mixture ofhexane and ethyl acetate, to give the title compound softening at72°-76° C.

Nuclear Magnetic Resonance Spectrum (CDCl₃) δ ppm:

1.41 (3H, singlet);

2.08 (3H, singlet);

2.17 (3H, singlet);

2.50 (3H, singlet);

2.88 δ 3.08 (2H, AB type, J=17 Hz);

3.00 (1H, doublet of doublets, J=9 δ 14 Hz);

3.42 (1H, doublet of doublets, J=4 δ 14 Hz);

3.92 (2H, singlet);

3.96 (3H, singlet);

4.2-4.9 (1broad);

4.45 (1H, doublet of doublets, J=4 δ 9 Hz);

6.83 (2H, doublet, J=9 Hz);

7.12 (2H, doublet, J=9 Hz).

EXAMPLE 255-{4-[4-(E)-Benzyloxyimino-6-hydroxy-2,5,7,8-tetramethylchroman-2-ylmethoxy]benzyl}thiazolidine-2,4-dione

A mixture of 1 g of5-[4-(6-hydroxy-2,5,7,8-tetramethyl-4-oxochroman-2-ylmethoxy)benzyl]thiazolidine-2,4-dione(prepared as described in Example 22 of copending U.S. Ser. No.644,996), 1.2 g of benzyloxylamine hydrochloride and 10 g of methanolwas allowed to stand for 7 days at room temperature. At the end of thistime, ethyl acetate and an aqueous solution of potassium carbonate wereadded. The organic layer was separated and dried over anhydrous sodiumsulfate. The solvent was distilled off and the residue was purified bysilica gel column chromatography eluted with a 3:1 by volume mixture ofhexane and ethyl acetate, to give the title compound, softening at64°-69° C.

Nuclear Magnetic Resonance Spectrum (CDCl₃) δ ppm:

1.40 (3H, singlet);

2.06 (3H, singlet);

2.16 (3H, singlet);

2.41 (3H, singlet);

2.92 δ 3.18 (2H, AB type, J=17 Hz);

3.02 (1H, doublet of doublets, J=9 δ 14 Hz);

3.42 (1H, doublet of doublets, J=4 δ 14 Hz);

3.90 (2H, singlet);

4.43 (b 1H, doublet of doublets, J=4 δ 9 Hz);

5.19 (2H, singlet);

6.82 (2H, doublet, J=9 Hz);

7.11 (2H, doublet, J=9 Hz);

7.2-7.5 (5H, multiplet).

EXAMPLE 265-{4-84-(E)-t-Butoxycarbonylmethoxyimino-6-hydroxy-2,5,7,8-tetramethylchroman-2-ylmethoxy]benzyl}thiazolidine-2,4-dione

A mixture of 1 g of5-[4-(6-hydroxy-2,5,7,8-tetramethyl-4-oxochroman-2-ylmethoxy)benzyl]thiazolidine-2,4-dione(prepared as described in Example 22 of copending U.S. Ser. No.644,996), 2.1 g of t-butoxycarbonylmethoxylammonium p-toluenesulfonate,5 g of methanol and 0.6 g of pyridine was allowed to stand for 7 days atroom temperature. At the end of this time, ethyl acetate and an aqueoussolution of potassium carbonate were added. The organic layer wasseparated and dried over anhydrous sodium sulfate. The solvent wasdistilled off and the residue was purified by silica gel columnchromatography eluted with a 3:1 by volume mixture of hexane and ethylacetate, to give the title compound, softening at 76°-80° C.

Nuclear Magnetic Resonance Spectrum (CDCl₃) δ ppm:

1.44 (3H, singlet);

1.49 (9H, singlet);

2.07 (3H, singlet);

2.17 (3H, singlet);

2.43 (3H, singlet);

3.02 (1H, doublet of doublets, J=9 δ 14 Hz);

3.08 (2H, AB type, J=17 Hz);

3.42 (1H, doublet of doublets, J=4 δ 14 Hz);

3.96 (2H, singlet);

4.43 (1H, doublet of doublets, J=4 δ 9 Hz);

4.57 (2H, singlet);

4.9-6.1 (2H, broad, disappeared on adding heavy water);

6.84 (2H, doublet, J=9 Hz);

7.10 (2H, doublet, J=9 Hz).

EXAMPLE 27 (a)5-[4-(6-Hydroxy-2,5,7,8-tetramethylchroman-2yl-methoxy)benzyl]-2-iminothiazolidin-4-oneand (b)5-[4-(6-hydroxy-2,5,7,8-tetramethylchroman-2-ylmethoxy)benzyl]thiazolidine-2,4-dione(Step A5)

A mixture of 9.6 g of ethyl3-[4-(6-acetoxy-2,5,7,8-tetramethylchroman-2-ylmethoxy)phenyl]-2-chloropropionate(prepared as described in Preparation 51), 1.8 g of thiourea and 11 mlof sulfolane was heated at 115°-120° C. for 80 minutes under a stream ofnitrogen. A mixture of 90 ml of acetic acid, 30 ml of concentratedhydrochloric acid and 15 ml of water was then added to the reactionmixture, which was then heated at 85°-90° C. for a further 12 hours. 27g of sodium bicarbonate were added to the reaction mixture, and, afterthe generation of carbon dioxide gas had ceased, the solvent wasdistilled off. A mixture of 10 parts by volume of benzene and 1 part ofethyl acetate was added to the crude residue, and the resulting solutionwas washed with a 1:1 by volume mixture of a saturated aqueous solutionof sodium bicarbonate and water. A white powdery product was collectedby filtration, washed with water and recrystallized from acetone to givethe title compound (a), melting at 205°-207° C.

Nuclear Magnetic Resonance Spectrum [DCON(CD₃)₂ +D₂ O] δ ppm:

1.37 (3H, singlet);

about 2 (2H, multiplet);

2.02 (3H, singlet);

2.14 (6H, singlet);

2.3-3.1 (adsorption signal of solvent);

3.42 (1H, doublet of doublets, J=15 δ 4.5 Hz);

4.60 (1H, doublet of doublets , J=9 δ 4.5 Hz);

6.93 (2H, doublet, J=9 Hz);

7.23 (2H, doublet, J=9 Hz).

The organic layer which was obtained after removal of the above whitepowder was washed with water and dried over anhydrous sodium sulfate.The solvent was distilled off and the resulting crude residue waspurified by silica gel column chromatography. After elution with a 10:1by volume mixture of benzene and ethyl acetate, the title compound (b)was obtained as a powder, melting at 184°-186° C., from the next elutionwith a 10:1.4 by volume mixture of benzene and ethyl acetate.

Nuclear Magnetic Resonance Spectrum [(CD₃)₂ CO] δ ppm:

1.39 (3H, singlet);

about 2 (2H, multiplet);

2.02 (3H, singlet);

2.09 (3H, singlet);

2.13 (3H, singlet);

2.63 (2H, broad triplet, J=6 Hz);

3.07 (1H, doublet of doublets, J=15 δ 9 Hz);

3.41 (1H, doublet of doublets, J=15 δ 4.5 Hz);

3.97 (2H, AB type, J=9 Hz);

4.70 (2H, doublet of doublets, J=9 δ 4.5 Hz);

6.90 (2H, doublet, J=9 Hz);

7.21 (2H, doublet, J=9 Hz).

EXAMPLE 285-[4-(6-Hydroxy-2,5,7,8-tetramethylchroman-2-ylmethoxy)benzyl]thiazolidine-2,4-dione(Step A5)

A mixture of 9.6 g of ethyl3-[4-(6-acetoxy-2,5,7,8-tetramethylchroman-2-ylmethoxy)phenyl]-2-chloropropionate(prepared as described in Preparation 51), 1.8 g of thiourea and 11 mlof sulfolane was heated for 3.5 hours at 120° C. under a nitrogenstream. 100 ml of ethylene glycol monomethyl ether and 70 ml of 10% w/vaqueous hydrochloric acid were then added to the reaction mixture, afterwhich it was heated under reflux for 12 hours. The product was thenpurified as described in Example 27, to give the title compound. Themelting point and nuclear magnetic resonance spectrum of this compoundaccorded with those of the compound obtained in Example 27(b).

EXAMPLE 295-[4-(7-t-Butyl-6-hydroxy-2-methylchroman-2-ylmethoxy)benzyl]thiazolidine-2,4-dione(Step A5)

Following the procedure described in Example 28, a mixture of 1.43 g ofethyl3-[4-(6-acetoxy-8-t-butyl-2-methylchroman-2-ylmethoxy)phenyl]-2-chloropropionate(prepared as described in Preparation 59), 430 mg of thiourea and 5 mlof sulfolane was heated for 3.5 hours at 120° C. 15 ml of ethyleneglycol monomethyl ether and 10 ml of 10% w/v aqueous hydrochloric acidwere then added to the reaction mixture, after which it was heated underreflux for 13 hours. The product was then separated and purified asdescribed in Example 27, to give the title compound as a slightly yellowpowder.

Rf value on silica gel thin layer chromatography=0.31 (developingsolvent, benzene:ethyl acetate=5:1 by volume).

Nuclear Magnetic Resonance Spectrum (CDCl₃) δ ppm:

1.37 (9H, singlet);

1.43 (3H, singlet);

1.63-2.30 (2H, multiplet);

2.67 (2H, broad triplet, J=7 Hz);

3.07 (1H, doublet of doublets, J=9 δ 15 Hz);

3.45 (1H, doublet of doublets, J=4 δ 15 Hz);

3.87 δ 3.97 (2H, AB type, J=9 Hz);

4.48 (1H, doublet of doublets, J=4 δ 9 Hz);

4.62 (1H, broad singlet, disappeared on adding heavy water);

6.41 (1H, singlet);

6.78 (1H, singlet);

6.88 (2H, doublet, J=9 Hz);

7.15 (2H, doublet, J=9 Hz);

8.40-8.93 (1H, broad, disappeared on adding heavy water).

5-[4-(4,6-Dihydroxy-2,5,7,8-tetramethylchroman-2-yl-methoxy)benzyl]thiazolidine-2,4-dione(Step H1)

450 mg of sodium borohydride were added to a mixture of 278 mg of5-[4-(6-hydroxy-2,5,7,8-tetramethyl-4-oxochroman-2-ylmethoxy)benzyl]thiazolidine-2,4-dione (prepared as described in Example 22 of copending U.S. Ser.No. 644,996) and 9 ml of methanol, and the mixture was stirred for 2hours at room temperature, after which a 1% w/v aqueous solution ofacetic acid was added and the mixture was neutralized with an aqueoussolution of potassium carbonate. It was then extracted with ethylacetate. The ethyl acetate extract was washed with water and dried overanhydrous sodium sulfate. The ethyl acetate was distilled from theextract under reduced pressure and the resulting residue was purified bysilica gel column chromatography, using a 5:3 by volume mixture ofhexane and ethyl acetate as eluent, to give the title compound, meltingat 102°-118° C.

Nuclear Magnetic Resonance Spectrum [(CD₃)₂ CO+D₂ O] δ ppm:

1.52 (3H, singlet);

2.01 (3H, singlet);

2.13 (3H, singlet: 2.29 (3H, singlet);

1.9-2.5 (1H, nd);

2.9-3.6 (2H, multiplet);

4.03 (2H, singlet);

3.9-4.5 (1H, nd);

4.6-5.1 (2H, multiplet);

6.7-7.4 (4H, nd).

EXAMPLE 31 (a)2-[4-(2,4-Dioxothiazolidin-5-ylmethyl)phenoxymethyl]-2,5,7,8-tetramethylchroman-6-ylhydrogen succinate

A mixture of 1.0 g of5-[4-(6-hydroxy-2,5,7,8-tetramethylchroman-2-ylmethoxy)benzyl]thiazolidine-2,4-dione (prepared as described in Example 28), 0.31 g of succinicanhydride and 1 ml of pyridine was allowed to stand overnight at roomtemperature. The reaction mixture was then washed 3 times, each timewith 10 ml of cyclohexane, and the insoluble residue obtained waspurified by silica gel column chromatography (eluted by mixtures ofbenzene and ethyl acetate ranging from 5:1 to 1:1) to give the titlecompound melting at 197°-202° C.

Nuclear Magnetic Resonance Spectrum (pentadeuterated pyridine) δ ppm:

1.36 (3H, singlet);

1.5-2.3 (2H, multiplet);

2.10 (6H, singlet);

2.14 (3H, singlet);

2.5 (2H, broad triplet, J=6 Hz);

2.7-3.35 (5H, multiplet;

3.60 (1H, doublet of doublets, J=4 δ 15 Hz);

3.95 δ 4.05 (2H, AB-type, J=9 Hz);

4.90 (1H, doublet of doublets, J=4 δ 9 Hz);

6.98 (2H, doublet, J=9 Hz);

7.30 (2H, doublet, J=9 Hz).

(b)2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]-2,5,7,8-tetramethylchroman-6-ylhydrogen succinate sodium salt

1 ml of a 2.5% w/v methanolic solution of sodium methoxide was added toa suspension of 246 mg of the compound obtained as described in (a)above in 100 ml of methanol at room temperature. Insoluble matter wasfiltered off, and then the methanol was distilled off under reducedpressure and the residue was washed with diethyl ether to give the titlecompound, melting at 178°-180° C.

EXAMPLE 325-[4-(6-Hydroxy-2,5,7,8-tetramethyl-2H-chromen-2-yl-methoxy)benzyl]thiazolidine-2,4-dione

A mixture of 140 mg of5-[4-(4,6-dihydroxy-2,5,7,8-tetramethylchroman-2-ylmethoxy)benzyl]thiazolidine-2,4-dione(prepared as described in Example 30), 10 mg of p-toluenesulfonic acid,10 ml of benzene and 0.5 ml of dimethylformamide was heated under refluxfor 1 hour. The reaction solution was cooled, washed with a saturatedaqueous solution of sodium bicarbonate and then with water and driedover anhydrous sodium sulfate. The solvent was distilled off underreduced pressure and the residue was purified by silica gel columnchromatography eluted with a 4:1 by volume mixture of benzene and ethylacetate, to give the title compound, softening at 173°-176° C.

Nuclear Magnetic Resonance Spectrum [(CD₃)₂ CO] δppm:

1.50 (3H, singlet);

2.02 (3H, singlet);

2.12 (3H, singlet);

2.18 (3H, singlet);

3.06 (1H, doublet of doublets, J=9 δ 14 Hz);

3.40 (1H, doublet of doublets, J=4 δ 14 Hz);

3.94 (1H, doublet, J=10 Hz);

4.05 (1H, doublet, J=10 Hz);

4.70 (1H, doublet of doublets, J=4 δ 9 Hz);

5.75 (1H, doublet, J=10 Hz);

6.72 (1H, doublet, J=10 Hz);

6.85 (2H, doublet, J=9 Hz);

7.19 (2H, doublet, J=9 Hz).

EXAMPLE 335-[4-(6-Hydroxy-2,5,7,8-tetramethylchroman-2-ylmethoxy)benzyl]thiazolidine-2,4-dione(Step H3)

Following the procedure described in Preparation 58, 120 mg of5-[4-(6-hydroxy-2,5,7,8-tetramethyl-2H-chromen-2-ylmethoxy)benzyl]thiazolidine-2,4-dione (prepared as described in Example 32) were dissolved in 4 mlof methanol and, in the presence of 40 mg of 10% w/wpalladium-on-carbon, it was reduced under 3-5 atmospheres (about 3-5bars) pressure of hydrogen, to give the title compound. The meltingpoint and nuclear magnetic resonance spectrum of this compound accordedwith those of the compound obtained in Example 27(b).

EXAMPLE 345-[4-(4-Carboxymethoxyimino-6-hydroxy-2,5,7,8-tetramethylchroman-2-ylmethoxy)benzyl]thiazolidine-2,4-dione

A mixture of 0.7 g of5-[4-(4-t-butoxycarbonylmethoxyimino-6-hydroxy-2,5,7,8-tetramethylchroman-2ylmethoxy)benzyl]thiazolidine-2,4-dione (prepared as described inExample 26) and 7 ml of a 4N dioxane solution of hydrogen chloride wasallowed to stand at room temperature for 15 hours. At the end of thistime, the solvent was distilled off and the residue was washed with warmwater to give the title compound, softening at 75°-85° C.

Nuclear Magnetic Resonance Spectrum ](CD₃)₂ SO]δ ppm:

1.33 (3H, singlet);

1.98 (3H, singlet);

2.09 (3H, singlet);

2.34 (3H, singlet);

2.9-3.5 (2H, multiplet);

3.0 (2H, singlet);

4.02 (2H, singlet);

4.65 (2H, singlet);

4.84 (1H, doublet of doublets, J=4 δ9 Hz);

6.90 (2H, doublet, J=9 Hz);

7.17 (2H, doublet, J=9 Hz);

7.55-7.95 (1H, broad, disappeared on adding heavy water).

EXAMPLE 35 2-Methoxyethylα-{2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]-2,5,7,8-tetramethyl-4-oxochroman-6-yloxy}acetate

A mixture of 13 g of ethyl3-[4-(6-t-butoxycarbonylmethoxy-2,5,7,8-tetramethyl-4-oxochroman-2-ylmethoxy)phenyl]-2-chloropropionate(prepared as described in Preparation 64), 2.6 g of thiourea and 15 mlof sulfolane was heated under a nitrogen stream at 120°-130° C. for 5hours. 30 ml of 2N aqueous hydrochloric acid and 60 ml of2-methoxyethanol were added to the resulting mixture, which was thenheated at 110° C. for 3 hours. The reaction mixture was then poured intowater and extracted with ethyl acetate. The extract was washed withwater and dried over anhydrous sodium sulfate. The solvent was distilledfrom the dried extract, and the residue was purified by silica gelcolumn chromatography (eluted with a 4:1 by volume mixture of benzeneand ethyl acetate) to give the title compound.

Rf value on silica gel thin layer chromatography=0.14 (developingsolvent, benzene:ethyl acetate=4:1 by volume).

Nuclear magnetic Resonance Spectrum (CDCl₃) δ ppm:

1.50 (3H, singlet);

2.10 (3H, singlet);

2.26 (3H, singlet);

2.45-2.8 (1H, nd);

2.56 (3H, singlet);

2.9-3.25 (1H, nd);

3.07 (1H, doublet, J=16 Hz);

3.40 (3H, singlet);

3.4-3.6 (1H, nd);

3.6-3.75 (2H, multiplet);

3.98 δ 4.11 (2H, AB type, J=10 Hz);

4.3-4.45 (2H, multiplet);

4.34 (2H, singlet);

4.45-4.6 (1H, nd);

6.85 (2H, doublet, J=9 Hz);

7.16 (2H, doublet, J=9 Hz);

8.7-9.3 (1H, broad).

EXAMPLE 365-[4-(6-Ethoxy-2,5,7,8-tetramethylchroman-2-ylmethoxy)benzyl]thiazolidine-2,4-dione

The title compound, melting at 56°-60° C., was obtained from 5.1 g ofethyl2-chloro-3-[4-(6-ethoxy-2,5,7,8-tetramethylchroman-2-ylmethoxy)phenyl]propionate(prepared as described in Preparation 65), 1 g of thiourea, 6 ml ofsulfolane, 16 ml of 2N aqueous hydrochloric acid and 5 ml of2-methoxyethanol, according to the same procedure as described inExample 35.

Mass spectrum (m/e): 469 (M⁺).

Nuclear Magnetic Resonance Spectrum (CDCl₃) δ ppm:

1.39 (3H, triplet, J=7 Hz);

1.41 (3H, singlet);

1.7-2.1 (2H, nd);

2.07 (3H, singlet);

2.14 (3H, singlet);

2.17 (3H, singlet);

2.61 (2H, broad triplet, J=7 Hz);

3.05 (1H, doublet of doublets, J=10 δ 14 Hz);

3.45 (1H, doublet of doublets, J=4 δ 14 Hz);

3.72 (2H, quartet, J=7 Hz);

3.87 δ 3.97 (2H, AB type, J=9 Hz);

4.47 (1H, doublet of doublets, J=4 δ 10 Hz);

6.87 (2H, doublet, J=9 Hz);

7.14 (2H, doublet, J=9 Hz);

8.6-8.8 (1H, broad, disappeared on adding heavy water).

EXAMPLE 37 2-Methoxyethylα-{2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]-4-hydroxy-2,5,7,8-tetramethylchroman-6-yloxy}acetate

1.5 g of sodium borohydride were added, whilst ice-cooling, to a mixtureof 1.2 g of 2-methoxyethylα-{2-[4-(2,4-dioxothiazolidin-5-ylmethyl)-phenoxymethyl]-2,5,7,8-tetramethyl-4-oxochroman-6-yloxy}acetate (prepared as described in Example 35) and 20 ml ofmethanol, and the mixture was stirred for 60 minutes. The reactionmixture was then poured into ice-water, neutralized with 10% w/v aqueoushydrochloric acid, and then extracted with ethyl acetate. The extractwas washed with water and dried over anhydrous sodium sulfate. Thesolvent was distilled off under reduced pressure to give the titlecompound as a pale yellow powder.

Rf value on silica gel thin layer chromatography=0.20 (developingsolvent, benzene:ethyl acetate=1:1 by volume).

Mass spectrum (m/e) : 573 (M⁺).

EXAMPLE 38 Methylα-{2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]-2,5,7,8-tetramethyl-2H-chromen-6-yloxy}acetate

A mixture of 970 mg of 2-methoxyethylα-{2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]4-hydroxy-2,5,7,8-tetramethylchroman-6-yloxy}acetate(prepared as described in Example 37), 50 mg of p-toluenesulfonic acid,10 ml of benzene and 1 ml of dioxane was heated under reflux in anitrogen stream for 60 minutes. The reaction mixture was then washedwith a 5% w/v aqueous solution of sodium bicarbonate and then withwater, and dried over anhydrous sodium sulfate. The solvent wasdistilled off under reduced pressure. The residue was purified by silicagel column chromatography (eluted with a 7:3 by volume mixture ofbenzene and ethyl acetate), to give the title compound.

Rf value on silica gel thin layer chromatography=0.74 (developingsolvent, benzene:ethyl acetate=1:1 by volume).

Nuclear Magnetic Resonance Spectrum [(CD₃)₂ CO]δ ppm:

1.51 (3H, singlet);

2.01 (3H, singlet);

2.14 (3H, singlet);

2.22 (3H, singlet);

3.07 (1H, doublet of doublets, J=9 δ 14 Hz);

3.42 (1H, doublet of doublets, J=4 δ 14 Hz);

3.74 (3H, singlet);

4.03 (2H, singlet);

4.32 (2H, singlet);

4.73 (1H, doublet of doublets, J=4 δ 9 Hz);

5.80 (1H, doublet, J=10 Hz);

6.70 (1H, doublet, J=10 Hz);

6.86 (2H, doublet, J=9 Hz);

7.20 (2H, doublet, J=9 Hz).

EXAMPLE 39 2-Methoxyethylα-{2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]-2,5,7,8-tetramethyl-2H-chromen-6-yloxy}acetate

The title compound was obtained from the fraction eluted after the onegiving the methyl ester in the column chromatography described inExample 38, using the same eluent.

Rf value on silica gel thin layer chromatography=0.59 (developingsolvent, benzene;ethyl acetate=1:1 by volume).

Nuclear Magnetic Resonance Spectrum [(CD₃)₂ CO]δ ppm:

1.52 (3H, singlet);

2.02 (3H, singlet);

2.16 (3H, singlet);

2.23 (3H, singlet);

3.09 (1H, doublet of doublets, J=9 δ 15 Hz);

3.30-3.60 (1H, nd);

3.32 (3H, singlet);

3.5-3.7 (2H, multiplet);

4.04 (2H, singlet);

4.25-4.45 (2H, multiplet);

4.35 (2H, singlet);

4.75 (1H, doublet of doublets, J=4 δ 9 Hz);

5.82 (1H, doublet, J=10 Hz);

6.72 (1H, doublet, J=10 Hz);

6.88 (2H, doublet, J=9 Hz);

7.21 (2H, doublet, J=9 Hz).

EXAMPLE 405-{4-[6-(2-Hydroxyethoxy)-2,5,7,8-tetramethyl-2H-chromen-2-ylmethoxy]benzyl}thiazolidine-2,4-dione

The title compound was obtained from the fraction eluted after the onegiving the 2-methoxyethyl ester in the silica gel column chromatographydescribed in Example 39, using the same eluent.

Rf value on silica gel thin layer chromatography=0.44 (developingsolvent, benzene:ethyl acetate=1:1 by volume).

Nuclear magnetic Resonance Spectrum [(CD₃)₂ CO]δ ppm:

1.51 (3H, singlet);

2.01 (3H, singlet);

2.15 (3H, singlet);

2.21 (3H, singlet);

3.08 (1H, doublet of doublets, J=9 δ 14 Hz);

3.42 (1H, doublet of doublets, J=4 δ 14 Hz);

3.6-3.95 (4H, multiplet);

4.03 (2H, singlet);

4.74 (1H, doublet of doublets, J=4 δ 9 Hz);

5.78 (1H, doublet, J=10 Hz);

6.71 (1H, doublet, J=10 Hz);

6.88 (2H, doublet, J=9 Hz);

7.21 (2H, doublet, J=9 Hz).

EXAMPLE 41 2-Methoxyethylα-{2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]-2,5,7,8-tetramethylchroman-6-yloxy}acetate

Using Paar's hydrogenation apparatus, a mixture of 260 mg of2-methoxyethylα-{2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]-2,5,7,8-tetramethyl-2H-chromen-6-yloxy}acetate(prepared as described in Example 39), 300 mg of 10% w/vpalladium-on-carbon and 50 ml of ethanol was stirred for 10 hours undera hydrogen pressure of 3-5 atmospheres. The palladium-on-carbon was thenfiltered off, and the filtrate was condensed by evaporation underreduced pressure, to give the title compound as a colorless oilysubstance.

Rf value on silica gel thin layer chromatography=0.34 (developingsolvent, benzene:ethyl acetate=2.1 by volume).

Nuclear magnetic Resonance Spectrum (CDCl₃) δ ppm:

1.40 (3H, singlet);

1.75-2.15 (2H, nd);

2.06 (3H, singlet);

2.14 (3H, singlet);

2.18 (3H, singlet);

2.61 (2H, broad triplet, J=7 Hz);

3.05 (1H, doublet of doublets, J=9 δ 14 Hz);

3.35-3.8 (3H, nd);

3.39 (3H, singlet);

3.86 δ 3.96 (2H, AB type, J=10 Hz);

4.25-4.6 (3H, nd);

4.34 (2H, singlet);

6.87 (2H, doublet, J=9 Hz);

7.15 (2H, doublet, J=9 Hz);

8.35-8.8 (1H, broad, disappeared on adding heavy water).

EXAMPLE 425-{4-[6-(2-Hydroxyethoxy)-2,5,7,8-tetramethylchroman-2-ylmethoxy]benzyl}thiazolidine-2,4dione

Following the same procedure as described in Example 41, 0.35 g of5-{4-[6-(2-hydroxyethoxy)-2,5,7,8-tetramethyl-2H-chromen-2-ylmethoxy]benzyl}-thiazolidine-2,4-dione(prepared as described in Example 40), 0.3 g of 10% w/w palladium onactivated carbon and 10 ml of ethanol gave the title compound.

Rf value on silica gel thin layer chromatography=0.45 (developingsolvent, benzene:ethyl acetate=1:1 by volume).

Nuclear magnetic Resonance Spectrum (CDCl₃) δ ppm:

1.41 (3H, singlet);

1.7-2.2 (2H, nd);

2.07 (3H, singlet);

2.13 (3H, singlet);

2.18 (3H, singlet);

2.61 (2H, broad triplet, J=7 Hz);

3.05 (1H, doublet of doublets, J=9 δ 14 Hz);

3.44 (1H, doublet of doublets, J=5 δ 14 Hz);

3.7-4.1 (6H, multiplet);

4.47 (1H, doublet of doublets, J=4 δ 9 Hz);

4.8-5.2 (2H, broad);

6.87 (2H, doublet, J=9 Hz);

7.14 (2H, doublet, J=9 Hz).

EXAMPLE 43 Ethylα-{2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]-2,5,7,8-tetramethyl-4-oxochroman-6-yloxy}acetate

A mixture of 0.5 g ofα-{2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]-2,5,7,8-tetramethyl-4-oxo-chroman-6-yloxy}aceticacid (obtained as described in Example 59), 0.5 ml of a 4N dioxanesolution of hydrogen chloride and 5 ml of ethanol was allowed to standovernight at room temperature. The reaction mixture was then poured intowater and the solution was neutralized with sodium bicarbonate andextracted with ethyl acetate. The extract was washed with water anddried over anhydrous sodium sulfate. The solvent was distilled off, andthe residue was subjected to preparative silica gel thin layerchromatography (developing solvent, benzene:ethyl acetate=7:3 by volume)to obtain the title compound.

Rf value on silica gel thin layer chromatography=0.70 (developingsolvent, benzene:ethyl acetate=1:1 by volume).

Nuclear Magnetic Resonance Spectrum (CDCl₃) δ ppm:

1.33 (3H, triplet, J=7 Hz);

1.50 (3H, singlet);

2.10 (3H, singlet);

2.26 (3H, singlet);

2.57 (3H, singlet);

2.55-2.8 (1H, nd);

3.06 (1H, doublet, J=16 Hz);

3.07 (1H, doublet of doublets, J=9 δ 14 Hz);

3.45 (1H, doublet of doublets, J=4 δ 14 Hz);

4.00 δ 4.11 (2H, AB type, J=10 Hz);

4.29 (2H, singlet);

4.31 (2H, quartet, J=7 Hz);

4.48 (1H, doublet of doublets, J=4 δ 9 Hz);

6.85 (2H, doublet, J=9 Hz);

7.16 (2H, doublet, J=9 Hz);

8.3-8.9 (1H, broad).

EXAMPLE 44 t-Butylα-{5-[4-(6-acetoxy-2,5,7,8-tetramethylchroman-2-ylmethoxy)benzyl]-2,4-dioxothiazolidin-3yl}acetate

0.87 g of t-butyl bromoacetate was added dropwise, whilst ice-cooling,to a mixture of 1 g of5-[4-(6-acetoxy-2,5,7,8-tetramethylchroman-2-ylmethoxy)benzyl]thiazolidine-2,4-dione [prepared as described in Example 3(b) ofcopending U.S. Ser. No. 644,996], 0.43 g of anhydrous potassiumcarbonate, and 8 ml of acetone. The resulting mixture was stirred for 2hours at room temperature and then allowed to stand for 2 days, also atroom temperature. The reaction mixture was then poured into ice-waterand extracted with ethyl acetate. The extract was washed with asaturated aqueous solution of sodium chloride and dried over anhydroussodium sulfate. The solvent was distilled off and the residue wassubjected to silica gel column chromatography (eluent:benzene) to givethe title compound.

Rf value on silica gel thin layer chromatography=0.6 (developingsolvent, benzene:ethyl acetate=10:1 by volume).

Nuclear Magnetic Resonance Spectrum (CDCl₃) δ ppm:

1.41 (3H, singlet);

1.47 (9H, singlet);

1.7-2.1 (2H, nd);

1.98 (3H, singlet);

2.02 (3H, singlet);

2.07 (3H, singlet);

2.30 (3H, singlet);

2.62 (2H, broad triplet, J=7 Hz);

2.98 (1H, doublet of doublets, J=10 δ 14 Hz);

3.55 (1H, doublet of doublets, J=4 δ 14 Hz);

3.86 δ 3.97 (2H, AB type, J=9 Hz);

4.19 (2H, singlet);

4.45 (1H, doublet of doublets, J=4 δ 10 Hz);

6.86 (2H, doublet J=9 Hz);

7.15 (2H, doublet, J=9 Hz).

EXAMPLE 45 Methylα-{5-[4-(6-acetoxy-2,5,7,8-tetramethylchroman-2-ylmethoxy)benzyl]-2,4-dioxothiazolidin-3-yl}acetate

Following the procedure described in Example 44, 2.4 g of5-[4-(6-acetoxy-2,5,7,8-tetramethylchroman-2-ylmethoxy)benzyl]thiazolidine-2,4-dione[prepared as described in Example 3(b) of copending U.S. Ser. No.644,996], 1.5 g of methyl bromoacetate, 1.5 g of potassium carbonate and25 ml of acetone gave the title compound as a colourless oil.

Rf value on silica gel thin layer chromatography=0.26 (developingsolvent, benzene:ethyl acetate=20:1 by volume).

Nuclear Magnetic Resonance Spectrum (CDCl₃) δ ppm:

1.42 (3H, singlet);

1.8-2.25 (2H, nd);

1.98 (3H, singlet);

2.02 (3H, singlet);

2.08 (3H, singlet);

2.30 (3H, singlet);

2.64 (2H, broad triplet, J=7 Hz);

3.01 (1H, doublet of doublets, J=10 δ 14 Hz);

3.54 (1H, doublet of doublets, J=4.5 δ 14 Hz);

3.75 (3H, singlet);

3.87 δ 4.00 (2H, AB type, J=9 Hz);

4.31 (2H, singlet);

4.50 (1H, doublet of doublets, J=4.5 δ 10 Hz);

6.89 (2H, doublet, J=9 Hz);

7.17 (2H, doublet, J=9 Hz).

EXAMPLE 46 t-butylα-{5-[4-(6hydroxy-2,5,7,8-tetramethylchroman-2-ylmethoxy)benzyl]-2,4-dioxothiazolidin-3-yl}acetate

Following the procedure described in Example 44, 1 g of5-[4-(6-hydroxy-2,5,7,8-tetramethylchroman-2-ylmethoxy)benzyl]thiazolidine-2,4-dione[prepared as described in Example 27(b)], 0.47 g of anhydrous potassiumcarbonate, 0.93 g of t-butyl bromoacetate and 8 ml of acetone gave thetitle compound.

Rf value on silica gel thin layer chromatography=0.52 (developingsolvent, benzene:ethyl acetate=10:1 by volume).

Nuclear Magnetic Resonance Spectrum (CDCl₃) δ ppm:

1.42 (3H, singlet);

1.48 (9H, singlet);

1.7-2.15 (2H, nd);

2.11 (6H, singlet);

2.16 (3H, singlet);

2.64 (2H, broad triplet, J=7 Hz);

2.99 (1H, doublet of doublets, J=10 δ 14 Hz);

3.56 (1H, doublet of doublets, J=4 δ 14 Hz);

3.85 δ 3.98 (2H, AB type, J=9 Hz);

4.21 (2H, singlet);

4.24 (1H, singlet);

4.46 (1H, doublet of doublets, J=4 δ 10 Hz);

6.88 (2H, doublet, J=9 Hz);

7.15 (2H, doublet, J=9 Hz).

EXAMPLE 47 Di-t-butylα,α'-{5-[4-(6-t-butoxycarbonylmethoxy-2,5,7,8-tetramethylchroman-2-ylmethoxy)benzyl]-2,4-dioxothiazolidine-3,5-diyl}diacetate

1.9 g of t-butyl bromoacetate was added dropwise, whilst ice-cooling, toa mixture of 1 g of5-[4-(6-hydroxy-2,5,7,8-tetramethylchroman-2-ylmethoxy)benzyl]thiazolidine-2,4-dione[prepared as described in Example 27(b)], 0.94 g of anhydrous potassiumcarbonate and 10 ml of acetone. The resulting mixture was stirred for 2days at room temperature. The reaction mixture was then poured intoice-water and extracted with benzene. The extract was washed with waterand dried over anhydrous sodium sulfate. The solvent was distilled offand the residue was subjected to silica gel column chromatography(eluent, benzene:ethyl acetate =20:1 by volume) to give the titlecompound.

Rf value on silica gel thin layer chromatography=0.54 (developingsolvent, cyclohexane:ethyl acetate=4:1 by volume).

Nuclear magnetic Resonance Spectrum (CDCl₃ δ ppm:

1.44 (9H, singlet);

1.48 (12H, singlet);

1.54 (9H, singlet);

1.8-2.1 (2H, nd);

2.07 (3H, singlet);

2.16 (3H, singlet);

2.20 (3H, singlet);

2.5-2.7 (2H, multiplet);

2.9-3.15 (2H, multiplet);

3.24 (2H, singlet);

3.93 (2H, broad singlet);

4.13 (2H, singlet);

4.17 (2H, singlet);

6.85 (2H, broad doublet, J=9 Hz);

7.15 (2H, broad doublet, J=9 Hz).

Mass Spectrum (m/e) : 783 (M⁺).

EXAMPLE 48t-Butyl-α-{55-[4-(6-t-butoxycarbonylmethoxy-2,5,7,8-tetramethylchroman-2-ylmethoxy)benzyl]-2,4-dioxothiazolidin-3-yl}acetate

In the column chromatography separation process described in Example 47,the title compound was obtained from the fractions eluted after thosegiving the t-butyl ester of Example 47, using the same eluent.

Rf value on silica gel thin layer chromatography=0.42 (developingsolvent, cyclohexane:ethyl acetate=4:1 by volume).

Nuclear Magnetic Resonance Spectrum (CDCl₃) δ ppm:

1.42 (3H, singlet);

1.48 (9H, singlet);

1.54 (9H, singlet);

1.7-2.1 (2H, nd);

2.06 (3H, singlet);

2.15 (3H, singlet);

2.19 (3H, singlet);

2.61 (2H, broad triplet, J=7 Hz);

2.99 (1H, doublet of doublets, J=10 δ 14 Hz);

3.56 (1H, doublet of doublets, J=4 δ 14 Hz);

3.87 δ 3.96 (2H, AB type, J=9 Hz);

4.17 (2H, singlet);

4.20 (2H, singlet);

4.46 (1H, doublet of doublets, J=4 δ 10 Hz);

6.87 (2H, doublet, J=9 Hz);

7.15 (2H, doublet, J=9 Hz).

Mass Spectrum (m/e) : 669 (M⁺).

EXAMPLE 49 t-Butylα-{5-[4-(6-hydroxy-2,5,7,8-tetramethyl-4-oxochroman-2-ylmethoxy)benzyl]-2,4-dioxothiazolidin-3-yl}acetate

Following the procedure described in Example 44, 1 g of5-[4-(6-hydroxy-2,5,7,8-tetramethyl-4-oxochroman-2-ylmethoxy)benzyl]thiazolidine-2,4-dione(prepared as described in Example 22 of copending U.S. Ser. No.644,996), 0.45 g of anhydrous potassium carbonate, 0.9 g of t-butylbromoacetate and 8 ml of acetone gave the title compound, softening at170°-180° C.

Nuclear Magnetic Resonance Spectrum [(CD₃)₂ CO]δ ppm:

1.46 (9H, singlet);

1.50 (3H, singlet);

2.10 (3H, singlet);

2.22 (3H, singlet);

2.5-2.8 (1H, nd);

2.54 (3H, singlet);

3.03 (1H, doublet of doublets, J=10 δ 14 Hz);

3.04 (1H, doublet, J=16 Hz);

3.53 (1H, doublet of doublets, J=4 δ 14 Hz);

4.16 (2H, singlet);

4.22 (2H, singlet);

4.82 (1H, doublet of doublets, J=4 δ 10 Hz);

6.96 (2H, doublet, J=9 Hz);

7.25 (2H, doublet, J=9 Hz).

EXAMPLE 50 Di-t-butylα,α'{5-[4-(6-t-butoxycarbonylmethoxy-2,5,7,8-tetramethyl-4-oxochroman-2-ylmethoxy)benzyl]-2,4-dioxothiazolidine-3,5-diyl}diacetate

Following the procedure described in Example 47, 1.5 g of5-[4-(6-hydroxy-2,5,7,8-tetramethyl-4-oxochroman-2-ylmethoxy)benzyl]thiazolidine-2,4-dione(prepared as described in Example 22 of copending U.S. Ser. No.644,996), 1.3 g of anhydrous potassium carbonate, 5.4 g of t-butylbromoacetate and 10 ml of acetone gave the title compound.

Rf value on silica gel thin layer chromatography=0.57 (developingsolvent, cyclohexane:ethyl acetate=7:3 by volume).

Nuclear Magnetic Resonance Spectrum (CDCl₃) δ ppm:

1.42 (9H, singlet);

1.46 (9H, singlet);

1.48 (3H, singlet);

1.52 (9H, singlet);

2.10 (3H, singlet);

2.26 (3H, singlet);

2.55-3.20 (4H, nd);

2.56 (3H, singlet);

3.23 (2H, singlet);

3.97 δ 4.08 (2H, AB type, J=10 Hz);

4.12 (2H, singlet);

4.16 (2H, singlet);

6.82 (2H, doublet, J=9 Hz);

7.15 (2H, doublet, J=9 Hz).

Mass spectrum (m/e): 797 (M⁺).

EXAMPLE 51 t-Butylα-{5-[4-(6-t-butoxycarbonylmethoxy-2,5,7,8-tetramethyl-4-oxochroman-2-ylmethoxy)benzyl]-2,4-dioxothiazolidin-3-yl}acetate

From the fraction eluted following the one giving di-t-butylα,α'-{5-[4-(6-t-butyloxycarbonylmethoxy-2,5,7,8-tetramethyl-4-oxochroman-2-ylmethoxy)benzyl]-2,4-dioxothiazolidine-3,5-diyl}diacetateas described in Example 50, the title compound was obtained, using thesame eluent.

Rf value on silica gel thin layer chromatography=0.46 (developingsolvent, cyclohexane:ethyl acetate=7:3 by volume).

Nuclear magnetic Resonance Spectrum (CDCl₃) δ ppm:

1.47 (9H, singlet);

1.50 (3H, singlet);

1.53 (9H, singlet);

2.10 (3H, singlet);

2.26 (3H, singlet);

2.56 (3H, singlet);

2.6-3.2 (3H, nd);

3.57 (1H, doublet of doublets, J=4 δ 14 Hz);

3.98 δ 4.11 (2H, AB type, J=10 Hz);

4.17 (2H, singlet);

4.20 (2H, singlet);

4.47 (1H, doublet of doublets, J=4 δ 10 Hz);

6.86 (2H, doublet, J=9 Hz);

7.16 (2H, doublet, J=9 Hz).

Mass spectrum (m/e): 683 (M⁺).

EXAMPLE 523-Ethyl-5-[4-(6-hydroxy-2,5,7,8-tetramethylchroman-2-ylmethoxy)benzyl]thiazolidine-2,4dione

Following the procedure described in Example 44, 0.58 g of5-[4-(6-hydroxy-2,5,7,8-tetramethylchroman-2-ylmethoxy)benzyl]thiazolidine-2,4-dione[prepared as described in Example 27(b)], 0.27 g of anhydrous potassiumcarbonate, 0.6 g of ethyl iodide and 5 ml of acetone gave the titlecompound.

Rf value on silica gel thin layer chromatography=0.30 (developingsolvent, benzene:ethyl acetate=20:1 by volume).

Nuclear magnetic Resonance Spectrum (CDCl₃) δ ppm:

1.09 (3H, triplet, J=7 Hz);

1.40 (3H, singlet);

1.7-2.2 (2H, nd);

2.09 (6H, singlet);

2.14 (3,singlet);

2.62 (2H, broad triplet, J=7 Hz);

3.02 (1h, doublet of doublets, J=9 δ 14 Hz);

3.25-3.5 (1H, nd);

3.59 (2H, quartet, J=7 Hz);

3.83 δ 3.96 (2H, AB type, J=10 Hz);

4.23 (1H, singlet, disappeared on adding heavy water);

4.36 (1H, doublet of doublets, J=4 δ 9 Hz);

6.84 (2H, doublet, J=9 Hz);

7.11 (2H, doublet, J=9 Hz).

EXAMPLE 53 t-Butylα-{5-[4-(6-hydroxy-4-hydroxyimino-2,5,7,8-tetramethylchroman-2-ylmethoxy)benzyl]-2,4-dioxothiazolidin-3-yl}acetate

A mixture of 0.5 g of t-butylα-{5-[4-(6-hydroxy-2,5,7,8-tetramethyl-4-oxochroman-2-ylmethoxy)benzyl]-2,4-dioxothiazolidin-3yl}acetate(prepared as described in Example 49), 0.25 g of hydroxylaminehydrochloride, 0.25 g of pyridine and 5 ml of methanol was allowed tostand t 25°-30° C. for 2 days. Ethyl acetate and an aqueous solution ofpotassium carbonate were added to the mixture, and the organic layer wasseparated. The organic layer was dried over anhydrous sodium sulfate.The solvent was distilled off and the residue was subjected to silicagel column chromatography (eluted with a 9:1 by volume mixture ofbenzene and ethyl acetate) to obtain the title compound.

Rf value on silica gel thin layer chromatography=0.55 (developingsolvent, benzene:ethyl acetate=4:1 by volume).

Nuclear Magnetic Resonance Spectrum [(CD₃)₂ CO]δ ppm:

1.42 (3H, singlet);

1.45 (9H, singlet);

2.07 (3H, singlet);

2.17 (3H, singlet);

2.46 (3H, singlet);

3.03 (1H, doublet of doublets, J=δ 13.5 Hz);

3.07 (2H, singlet);

3.55 (1H, doublet of doublets, J=4 δ 13.5 Hz);

4.06 (2H, singlet);

4.18 (2H, singlet);

4.83 (1H, doublet of doublets, J=4 δ 10 Hz);

6.94 (2H, doublet, J=9 Hz);

7.25 (2H, doublet, J=9 Hz);

10.2 (1H, broad singlet, disappeared adding heavy water).

EXAMPLE 54 2-Methoxyethylα-{2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl-4-hydroxyimino-2,5,7,8-tetramethylchroman-6-yloxy}acetate

A mixture of 0.6 g of 2-methoxyethylα-{2-[49(2,4-dioxothiazolidin-5-oxochroman-6-yloxy {acetate (prepared asdescribed in Example 35), 0.3 g of hydroxylamine hydrochloride, 0.3 g ofpyridine and 6 ml of methanol was allowed to stand at 25°-30 ° C. for 2days. Ethyl acetate and an aqueous solution of potassium carbonate wereadded to the mixture, and the organic layer was separated. The organiclayer was dried over anhydrous sodium sulfate. The solvent was distilledoff and the residue was subjected to silica gel column chromatography(eluted with a 7:3 by volume mixture of benzene and ethyl acetate) toobtain the title compound.

Rf value on silica gel thin layer chromatography=0.32 (tailing)(developing solvent, benzene:ethyl acetate=3:2 by volume).

Nuclear Magnetic Resonance Spectrum [(CD₃)₂ CO]δ ppm:

1.43 (3H, singlet);

2.06 (3H, singlet);

2.20 (3H, singlet);

2.46 (3H, singlet);

2.8-3.55 (2H, nd);

3.10 (2H, AB type, J=13.5 Hz);

3.32 (3H, singlet);

3.55-3.7 (2H, multiplet);

4.08 (2H, AB type, J=6 Hz);

4.25-4.4 (2H, multiplet);

4.34 (2H, singlet);

4.76 (1H, doublet of doublets, J=4 δ 9 Hz);

6.93 (2H, doublet, J=9 Hz);

7.24 (2H, doublet, J=9 Hz);

10.0-10.6 (1H, broad, disappeared on adding heavy water).

EXAMPLE 55 t-Butylα-{5-[4-(6-t-butoxycarbonylmethoxy-4-hydroxyimino-2,5,7,8-tetramethylchroman-2-ylmethoxy)benzyl]-2,4-dioxothiazolidin-3-yl}acetate

A mixture of 0.5 g of t-butylα-{5-[4-(6-t-butoxycarbonylmethoxy-2,5,7,8-tetramethyl-4-oxochroman-2-ylmethoxy)benzyl]-2,4-dioxothiazolidin-3-yl}acetate(prepared as described in Example 51), 0.2 g of hydroxylaminehydrochloride, 0.2 g of pyridine and 5 ml of methanol was allowed tostand at 25°-30° C. for 5 days. Ethyl acetate and an aqueous solution ofpotassium carbonate were added to the mixture, and the organic layer wasseparated. The organic layer was dried over anhydrous sodium sulfate.The solvent was distilled off and the residue was subjected to silicagel column chromatography (eluted with a 20:1 by volume mixture ofbenzene and ethyl acetate) to obtain the title compound.

Rf value on silica gel thin layer chromatography=0.43 (developingsolvent, benzene:ethyl acetate=10:1 by volume).

Nuclear Magnetic Resonance Spectrum (CDCl₃) δ ppm:

1.45 (3H, singlet);

1.47 (9H, singlet);

1.54 (9H, singlet);

2.07 (3H, singlet);

2.23 (3H, singlet);

2.47 (3H, singlet);

2.85-3.15 (1H, nd);

3.08 (2H, singlet);

3.57 (1H, doublet of doublets, J=4 δ 13.5 Hz);

3.97 (2H, singlet);

4.20 (4H, singlet);

4.46 (1H, doublet of doublets, J=4 δ 9 Hz);

6.87 (2H, doublet, J=9 Hz);

7.15 (2H, doublet, J=9 Hz);

7.5-8.05 (1H, broad).

EXAMPLE 56 Di-t-butylα,α'-{5-[4-(6-t-butoxycarbonylmethoxy-4-hydroxyimino-2,5,7,8-tetramethylchroman-2-ylmethoxy)benzyl]-2,4-dioxothiazolidine-3,5-diyl}diacetate

A mixture of 350 mg of di-t-butylα,α'-{5-[4-(6-t-butoxycarbonylmethoxy-2,5,7,8-tetramethyl-4-oxochroman-2-ylmethoxy)benzyl]-2,4-dioxothiazolidine-3,5-diyl}diacetate(prepared as described in Example 50), 122 mg of hydroxylaminehydrochloride, 122 mg of pyridine and 4 ml of methanol was allowed tostand at 25°-+° C. for 5 days. Ethyl acetate and an aqueous solution ofpotassium carbonate were added to the mixture, and the organic layer wasseparated. The organic layer was dried over anhydrous sodium sulfate.The solvent was distilled off and the residue was subjected to silicagel column chromatography (eluted with a 20:1 by volume mixture ofbenzene and ethyl acetate) to obtain the title compound.

Rf value on silica gel thin layer chromatography=0.48 (developingsolvent, benzene:ethyl acetate=10:1 by volume).

Nuclear Magnetic Resonance Spectrum (CDCl₃) δ ppm:

1.45 (21H, singlet);

1.53 (9H, singlet);

2.08 (3H, singlet);

2.23 (3H, singlet);

2.47 (3H, singlet);

2.9-3.2 (1H, nd);

3.07 (2H, broad singlet);

3.22 (2H, singlet);

3.95 (2H, broad singlet);

4.11 (2H, singlet);

4.18 (2H, singlet);

6.83 (2H, doublet, J=9 Hz);

7.13 (2H, doublet, J=9 Hz);

7.68 (1H, broad singlet).

EXAMPLE 57 Ethylα-{2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]-4-hydroxyimino-2,5,7,8-tetramethylchroman-6-yloxy}acetate

Following the procedure described in Example 54, the title compound wasobtained as a pale yellow powder by using 330 mg of ethylα-{2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]-2,5,7,8tetramethyl-4-oxochroman-6-yloxy}acetate (prepared as described in Example 43), 170mg of hydroxylamine hydrochloride, 170 mg of pyridine and 3 ml ofmethanol.

Rf value on silica gel thin layer chromatography =0.67 (developingsolvent, benzene:ethyl acetate=1:1 by volume).

Mass spectrum (m/e): 556 (M⁺).

Nuclear Magnetic Resonance Spectrum [(CD₃)₂ CO]δ ppm:

1.27 (3H, triplet, J=7 Hz);

1.43 (3H, singlet);

2.06 (3H, singlet);

2.20 (3H, singlet);

2.46 (3H, singlet);

2.95-3.25 (1H, nd);

3.08 (2H, singlet);

3.43 (1H, doublet of doublets, J=4 δ 14 Hz);

4.08 (2H, singlet);

4.1-4.4 (2H, nd);

4.30 (2H, singlet);

4.74 (1H, doublet of doublets, J=4 δ 9 Hz);

6.93 (2H, doublet, J=9 Hz);

7.23 (2H, doublet, J=9 Hz);

10.30 (1H, broad singlet, disappeared on adding heavy water).

EXAMPLE 58α-{2-[4-(2,4-Dioxothiazolidin-5-ylmethyl)phenoxymethyl]-2,5,7,8-tetramethylchroman-6yloxy}aceticacid

A mixture of 220 mg of 2-methoxyethylα-{2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl)92,5,7,8-tetramethylchroman-6-yloxy}acetate (prepared as described inExample 41), 3 ml of a 4N dioxane solution of hydrogen chloride and 0.3ml of water was heated under reflux for 5 hours. At the end of thistime, the solvent was distilled off and the residue was washed withwater to give the title compound as a pale yellow powder.

Nuclear Magnetic Resonance Spectrum [(CD₃)₂ CO]δ ppm:

1.38 (3H, singlet);

1.8-2.2 (2H, nd);

2.02 (3H, singlet);

2.15 (6H, singlet);

2.65 (2H, broad triplet, J=7 Hz);

3.08 (1H, doublet of doublets, J=9 δ 14 Hz);

3.41 (1H, doublet of doublets, J=4 δ 14 Hz);

4.00 (2H, singlet);

4.27 (2H, singlet);

4.73 (1H, doublet of doublets, J=4 δ 9 Hz);

6.92 (2H, doublet, J=9 Hz);

7.23 (2H, doublet, J=9 Hz);

9.9-11.3 (1H, broad, disappeared on adding heavy water).

Mass spectrum (m/e): 499 (M⁺).

EXAMPLE ∇

α-{2-[4-(2,4-Dioxothiazolidin-5-ylmethyl)-phenoxymethyl]-2,5,7,8-tetramethyl-4-oxochroman-6-yloxy}acetic acid

After eluting the 2-methoxyethyl ester which was obtained from thesilica gel column chromatography described in Example 35, the titlecompound was obtained as pale yellow powder by continuing the elutionwith a 2:2:1 by volume mixture of ethyl acetate, tetrahydrofuran andmethanol.

Nuclear Magnetic Resonance Spectrum [(CD₃)₂ SO]δ ppm:

1.41 (3H, singlet);

2.02 (3H, singlet);

2.18 (3H, singlet);

2.46 (3H, singlet);

2.68 (1H, doublet, J=16 Hz);

2.85-3.20 (2H, nd);

3.22 (1H, doublet of doublets, J=4 δ 14 Hz);

4.01 (2H, singlet);

4.12 (2H, singlet);

4.61 (1H, doublet of doublets, J=4 δ 9 Hz);

6.87 (2H, doublet, J=9 Hz);

7.15 (2H, doublet, J=9 Hz).

Mass spectrum (m/e): 513 (M⁺).

EXAMPLE 60α-{2-[4-(2,4-Dioxothiazolidin-5-ylmethyl)phenoxymethyl]-4-hydroxyimino-2,5,7,8-tetramethylchroman-6-yloxy}aceticacid

A mixture of 8.9 mg of ethylα-{2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]-4-hydroxyimino-2,5,7,8-tetramethylchroman-6-yloxy}acetate[prepared as described in Example 57], 1 ml of ethanol and 0.2 ml of a0.312M aqueous solution of sodium hydroxide was allowed to stand for 19hours at 0°-5° C.

After the absence of the starting material had been confirmed by highpressure liquid chromatography, 0.56 ml of 0.35% w/v aqueoushydrochloric acid was then added to the reaction mixture. The solventwas distilled off under reduced pressure, and chloroform and water wereadded to the residue.

The pale yellow precipitate was filtered and then washed with water, togive the title compound.

Fast Atom Bombardment Mass Spectrum (m/e measured with glycerol as amatrix)

[M+H]⁺ =529.

[M-H]⁻ =527.

From the above data, the molecular weight was deduced to be 528.

EXAMPLE 61α-{5-[4-(6-Hydroxy-2,5,7,8-tetramethylchroman-2-yl-methoxy)benzyl]-2,4-dioxothiazolidin-3yl}acetic acid

A mixture of 1.0 g of t-butylα-{5-[4-(6-hydroxy-2,5,7,8-tetramethylchroman-2-ylmethoxy)benzyl]-2,4-dioxothiazolidin-3-yl}acetate (prepared as described in Example46) and 10 ml of a 4N dioxane solution of hydrogen chloride was allowedto stand at room temperature overnight. At the end of this time, thesolvent was distilled off and the residue was washed with water to givethe title compound as a pale yellow powder, softening at 85°-90° C.

Nuclear magnetic Resonance Spectrum: the signal assigned to the t-butylgroup had disappeared, as compared with the spectrum of the startingmaterial.

Mass spectrum (m/e): 499 (M⁺).

EXAMPLE 62α-{5-[4-(6-Hydroxy-2,5,7,8-tetramethyl-4-oxochroman-2-ylmethoxy)benzyl]-2,4-dioxothiazolidin-3-yl}aceticacid

A mixture of 350 mg of t-butylα-{5-[4-(6-hydroxy-2,5,7,8-tetramethyl-4-oxochroman-2-ylmethoxy)benzyl]-2,4-dioxothiazolidin-3yl}acetate(prepared as described in Example 49) and 4 ml of a 4N dioxane solutionof hydrogen chloride was treated in the same manner described in Example61, to give the title compound as a pale yellow powder, softening at60°-70° C.

Nuclear Magnetic Resonance Spectrum: the signal assigned to the t-butylgroup had disappeared, as compared with the spectrum of the startingmaterial.

Mass spectrum (m/e): 513 (M⁺).

EXAMPLE 63α-{5-[4-(6-Hydroxy-4-hydroxyimino-2,5,7,8-tetramethylchroman-2-ylmethoxy)benzyl]-2,4-dioxothiazolidin-3-yl}aceticacid

A mixture of 400 mg of t-butylα-{5-[4-)6-hydroxy-4-hydroxyimino-2,5,7,8-tetramethylchroman-2-ylmethoxy)benzyl]-2,4-dioxothiazolidin-3-yl}acetate (prepared asdescribed in Example 53) and 5 ml of a 4N dioxane solution of hydrogenchloride was treated in the same manner described in Example 61, to givethe title compound as a pale brown powder, softening at 90°-95° C.

Nuclear Magnetic Resonance Spectrum: the signal assigned to the t-butylgroup had disappeared, as compared with the spectrum of the startingmaterial.

EXAMPLE 64α-{5-[4-(6-Carboxymethoxy-2,5,7,8-tetramethylchroman-2-ylmethoxy)benzyl]-2,4-dioxothiazolidin-3-yl}acetic acid

A mixture of 0.63 g of t-butylα-{5-[4-(6-t-butoxycarbonylmethoxy-2,5,7,8-tetramethylchroman-2-ylmethoxy)benzyl]-2,4-dioxothiazolidin-3-yl}acetate(prepared as described in Example 48) and 6 ml of a 4N dioxane solutionof hydrogen chloride was allowed to stand at room temperature overnight.At the end of this time, the reaction mixture was treated as the samemanner described in Example 61, to give the title compound as a paleyellow powder, softening at 95°-100° C.

Nuclear Magnetic Resonance Spectrum: the signal assigned to the t-butylgroup had disappeared, as compared with the spectrum of the startingmaterial.

Mass spectrum (m/e): 557 (M⁺).

EXAMPLE 65α-{5-[4-(6-Carboxymethoxy-2,5,7,8-tetramethyl-4-oxochroman-2-ylmethoxy)benzyl]-2,4-dioxothiazolidin-3-yl}aceticacid

A mixture of 570 mg of t-butylα-{5-[4-(6-t-butoxycarbonylmethoxy-2,5,7,8-tetramethyl-4-oxochroman-2-ylmethoxy)benzyl]-2,4-dioxothiazolidin3-yl}acetate(prepared as described in Example 51) and 6 ml of a 4N dioxane solutionof hydrogen chloride was treated in the same manner described in Example61, to give the title compound as a pale yellow powder, softening at80°-85° C.

Nuclear Magnetic Resonance Spectrum: the signal assigned to the t-butylgroup had disappeared, as compared with the spectrum of the startingmaterial.

Mass spectrum (m/e): 571 (M⁺).

EXAMPLE 66α-{5-[4-(6-Carboxymethoxy-4-hydroxyimino-2,5,7,8-tetramethylchroman-2-ylmethoxy)benzyl]-2,4-dioxothiazolidin-3-yl}aceticacid

A mixture of 370 mg of t-butylα-{5-[4-(6-t-butoxycarbonylmethoxy-4-hydroxyimino-2,5,7,8-tetramethylchroman-2-ylmethoxy)benzyl]-2,4-dioxothiazolidin-3-yl}acetate(prepared as described in Example 55) and 4 ml of a 4N dioxane solutionof hydrogen chloride was treated in the same manner described in Example61, to give the title compound as a pale yellow powder, softening at90°-100° C.

Nuclear Magnetic Resonance Spectrum: the signal assigned to the t-butylgroup had disappeared, as compared with the spectrum of the startingmaterial.

EXAMPLE 67α,α'-{5-[4-(6-Carboxymethoxy-2,5,7,8-tetramethylchroman-2-ylmethoxy)benzyl]-2,4-dioxothiazolidine-3,5-diyl}diaceticacid

A mixture of 0.41 g of di-t-butylα,α'-{5-[4-(6-t-butoxycarbonylmethoxy-2,5,7,8-tetramethylchroman-2-ylmethoxy)benzyl]-2,4-dioxothiazolidine-3,5-diyl}diacetate(prepared as described in Example 47) and 4 ml of a 4N dioxane solutionof hydrogen chloride was allowed to stand at room temperature overnight.At the end of this time, the reaction mixture was treated in the samemanner described in Example 61, to give the title compound as a paleyellow powder, softening at 105°-110° C.

Nuclear Magnetic Resonance Spectrum: the signal assigned to the t-butylgroup had disappeared, as compared with the spectrum of the startingmaterial.

Mass spectrum (m/e): 615 (M⁺).

EXAMPLE 68α,α'-{5-[4-(6-Carboxymethoxy-2,5,7,8-tetramethyl-4-oxochroman-2-ylmethoxy)benzyl]-2,4-dioxothiazolidine-3,5-diyl}diaceticacid

A mixture of 340 mg of di-t-butylα,α'-{5-[4-(6-t-butoxycarbonylmethoxy-2,5,7,8-tetramethyl-4-oxochroman-2-ylmethoxy)benzyl]-2,4-dioxothiazolidine-3,5-diyl}diacetate(prepared as described in Example 50) and 4 ml of a 4N dioxane solutionof hydrogen chloride was treated in the same manner described in Example61, to give the title compound as a pale yellow powder, softening at105°-110° C.

Nuclear Magnetic Resonance Spectrum: the signal assigned to the t-butylgroup had disappeared, as compared with the spectrum of the startingmaterial.

Mass Spectrum (m/e): 629 (M⁺).

EXAMPLE 69α,α'-{5-[4-(6-Carboxymethoxy-4-hydroxyimino-2,5,7,8-tetramethylchroman-2-ylmethoxy)benzyl]-2,4-dioxothiazolidine-3,5-diyl}diacetic acid

A mixture of 270 mg of di-t-butylα,α'-{5-[4-(6-t-butoxycarbonylmethoxy-4-hydroxyimino-2,5,7,8-tetramethylchroman-2-ylmethoxy)benzyl]-2,4-dioxothiazolidine-3,5-diyl}diacetate(prepared as described in Example 56) and 3 ml of a 4N dioxane solutionof hydrogen chloride was treated in the same manner described in Example61, to give the title compound as a pale yellow powder, softening at90°-100° C.

Nuclear Magnetic Resonance Spectrum: the signal assigned to the t-butylgroup had disappeared, as compared with the spectrum of the startingmaterial.

EXAMPLE 705-[4-(6-Hydroxy-2,5,7,8-tetramethylchroman-2-ylmethoxy)benzyl]thiazolidine-2,4-dionesulfuric acid ester

A solution of 5 g of5-[4-(6-hydroxy-2,5,7,8-tetramethylchroman-2-ylmethoxy)benzyl]thiazolidine-2,4-dione (synthesized as described in copending U.S. Ser. No. 644,996)in 10 ml of pyridine was added to a solution of 7.3 g (62.64 mmole) ofchlorosulfonic acid in 20 ml of pyridine, and the reaction mixture washeated at 70°-80° C. for 1 hour. At the end of this time, petroleumether was added to the reaction mixture, the supernatant liquid wasremoved by decantation, and then these procedures were repeated afurther 2 times. 10 ml of water were added to the resulting residue. Thereaction mixture was adjusted to a pH value of 6.5 with a 2N aqueoussolution of sodium hydroxide and extracted with ethyl acetate. The ethylacetate was distilled from the extract under reduced pressure, to give5.72 g of the title compound as a white powder, melting at 140.5°142.5°C.

Infrared Absorption Spectrum (Nujol-trade mark-mull): ν_(max) cm⁻¹ :

3600, 3330, 1270, 1050.

Nuclear Magnetic Resonance Spectrum:(CD₃ CN) δ ppm:

7.2 (2H, doublet);

6.9 (2H, doublet);

4.6 (1H, doublet of doublets);

4.0 (1H, doublet);

3.9 (1H, doublet);

3.3 (1H, doublet of doublets);

3.1 (1H, doublet of doublets);

2.6 (2H, triplet);

2.19 (3H, singlet);

2.18 (3H, singlet);

2.1 (1H, multiplet);

2.0 (3H, singlet);

1.9 (1H, multiplet);

1.4 (3H, singlet).

Fast Atom Bombardment Mass Spectrum (m/e measured with glycerol as amatrix)

(M+H)⁺ =522;

(M-H)⁻ =520.

From this, we concluded that molecular weight is 521.

PREPARATION 1 Ethyl 6-hydroxy-5,7,8-trimethyl-4-oxochroman-2-carboxylate(Step E1)

12 g of ethyl 6-hydroxy-5,7,8-trimethyl-4-oxo-2H-chromene-2-carboxylate[prepared as described in J. Med Chem., 18, 934 (1975)] were dissolvedin 250 ml of dimethylformamide and reduced catalytically in the presenceof 16 g of 10% w/w palladium-on-carbon, under a hydrogen pressure of 5atmospheres at 50° to 60° C. for 7 hours. The catalyst was then filteredoff, and the filtrate was mixed with a large amount of water. Thecrystals which separated were collected by filtration and thenrecrystallized from ethyl acetate, to give the title compound, meltingat 120°-121° C.

Nuclear Magnetic Resonance Spectrum (CDCl₃) δ ppm:

1.26 (3H, triplet, J=7 Hz);

2.23 (6H, singlet);

2.52 (3H, singlet);

2.98 (2H, doublet, J=7 Hz);

4.24 (2H, quartet, J=7 Hz);

4.83 (1H, singlet);

4.94 (1H, triplet, J=7 Hz).

The filtrate from which the title compound had been filtered off wasextracted with ethyl acetate. The solution was dried over anhydroussodium sulfate, and the solvent was distilled off. The residue waspurified by silica gel column chromatography, eluted with a 1:1 byvolume mixture of hexane and ethyl acetate. The first fraction gave thetitle compound, while the second fraction gave ethyl4,6-dihydroxy-5,7,8-trimethylchroman-2-carboxylate, melting at 138°-144° C.

PREPARATION 2 Ethyl6-hydroxy-5,7,8trimethylchromanspiro-4,2'-(1',3'-dithiane)-2-carboxylate(Step E2)

20 ml of a boron trifluoride-acetic acid complex salt (boron trifluoridecontent 40% w/w) were added dropwise to 500 ml of a chloroform solutioncontaining 16.6 g of ethyl6-hydroxy-5,7,8-trimethyl-4-oxochroman-2-carboxylate (prepared asdescribed in Preparation 1) and 9.7 g of 1,3-propanedithiol in an icebath, and the reaction mixture was allowed to stand for 24 hours at roomtemperature. The reaction mixture was then poured into ice-water,neutralized with potassium carbonate and extracted with ethyl acetate.The ethyl acetate extract was dried over anhydrous sodium sulfate andthe solvent was distilled off. Recrystallization of the residue fromethyl acetate afforded the title compound, melting at 186°-188° C.

Nuclear Magnetic Resonance Spectrum (CDCl₃) δ ppm:

1.35 (3H, triplet, J=7 Hz);

1.8-2.4 (2H, nd);

2.18 (6H, singlet);

2.5-2.9 (3H, nd);

2.80 (3H, singlet);

3.0-3.5 (3H, multiplet);

4.31 (2H, quartet, J=7 Hz);

4.50 (1H, singlet);

4.79 (1H, doublet of doublets, J=2 δ 10 Hz).

PREPARATION 3 Ethyl 6methoxymethoxy-5,7,8-trimethylchromanspiro-4,2'-(1',3'-dithiane)-2-carboxylate(Step E3)

A mixture of 6.6 g of ethyl6-hydroxy-5,7,8-trimethylchromanspiro-4,2'-(1',3'-dithiane)-2-carboxylate(prepared as described in Preparation 2), 100 ml of dimethylformamideand 1 g of a 55% w/w suspension of sodium hydride in mineral oil wassubjected to ultrasonic treatment for mixing at room temperature for 1hour, and then, whilst ice-cooling, 3 g of chloromethyl methyl etherwere added, and the mixture was allowed to stand at room temperatureovernight. Water was added to the reaction mixture, which was thenextracted with ethyl acetate. The water layer was extracted additionallywith benzene. Both the ethyl acetate and benzene extracts were washedwith water three times, after which the extracts were combined and driedover anhydrous sodium sulfate. The solvent was distilled off and theresidue was purified by silica gel column chromatography, eluted with a5:1 by volume mixture of hexane and ethyl acetate, to give the titlecompound.

Rf value on silica gel thin layer chromatography=0.21 (developingsolvent, hexane:ethyl acetate=5:1 by volume).

Nuclear Magnetic Resonance Spectrum (CDCl₃) δ ppm:

1.34 (3H, triplet, J=7 Hz);

1.7-2.4 (2H, nd);

2.16 (3H, singlet);

2.21 (3H, singlet);

2.5-3.0 (3H, nd);

2.87 (3H, singlet);

3.0-3.5 (3H, nd);

3.60 (3H, singlet);

4.30 (2H, quartet, J=7 Hz);

4.7-5.0 (1H, nd);

4.89 (2H, singlet).

PREPARATION 42-Hydroxymethyl-2-isobutyl-6-methoxymethoxy-5,7,8-trimethylchromanspiro-4,2'-(1',3'-dithiane)(Steps E4 & E5)

15 ml of a hexane solution of butyllithium (butyllithium content 1.62mmole/ml) were added dropwise at a temperature of -60° C. to -50° C. to90 ml of a tetrahydrofuran solution containing 3 g of diisopropylamine,and the mixture was allowed to stand for 20 minutes at room temperature.4.8 g of ethyl6-methoxymethoxy-5,7,8-trimethylchromanspiro-4,2'-(1',3'-dithiane)-2-carboxylate(prepared as described in Preparation 3) were added at -60° C. to themixture, which was then stirred for 10 minutes at the same temperature.4.1 g of isobutyl bromide were added, and the mixture was stirred for 30minutes at the same temperature, and then stirred at room temperaturefor 1.5 hours. Another 3 g of isobutyl bromide were added, and themixture was heated at 40° C. for 5 hours. The reaction mixture was thencooled to -50° C., 0.6 g of lithium aluminum hydride were added, and themixture was stirred for 1 hour at room temperature. Benzene, ethylacetate and water were added to this reaction mixture. The organic layerwas separated, washed with water and dried over anhydrous sodiumsulfate. The solvent was distilled off under reduced pressure. Theresidue was purified by silica gel column chromatography, eluted with a5:1 by volume mixture of hexane and ethyl acetate, to give the titlecompound.

Rf value on silica gel thin layer chromatography=0.16 (developingsolvent, hexane:ethyl acetate=5:1 by volume).

Nuclear Magnetic Resonance Spectrum (CDCl₃) δ ppm:

1.03 (3H, doublet, J=6 Hz);

1.04 (3H, doublet, J=6 Hz);

1.70 (2H, doublet, J=6 Hz);

1.8-2.3 (3H, nd);

2.08 (3H, singlet);

2.20 (3H, singlet);

2.3-3.0 (4H, nd);

2.91 (3H, singlet);

3.05-3.95 (5H, nd);

3.62 (3H, singlet);

4.88 (2H, singlet).

PREPARATION 52-Isobutyl-6-methoxymethoxy-5,7,8-trimethyl-2-(4-nitrophenoxymethyl)chromanspiro-4,2'-(1',3'-dithiane)(Step E6)

4 ml of ethanol were added to a mixture of 0.6 g of a 55% w/w suspensionof sodium hydride in mineral oil and 20 ml of tetrahydrofuran, followedby 20 ml of a tetrahydrofuran solution containing 3.2 g of2-hydroxymethyl-2-isobutyl-6-methoxymethoxy-5,7,8-trimethylchromanspiro-4,2'-(1',3'-dithiane)(prepared as described in Preparation 4). The solvent was then distilledoff under reduced pressure to dryness. The residue was mixed with 30 mlof dimethylformamide and heated at 40° C. for 1 hour under reducedpressure. 10 g of p-nitrochlorobenzene were then added to the reactionmixture, and the mixture was heated at 50° C. for 2 hours, mixed withwater and extracted with benzene. The benzene extract was washed twicewith water and dried over anhydrous sodium sulfate. The solvent wasdistilled off under reduced pressure. The residue was purified by silicagel column chromatography eluted with a 6:1 by volume mixture of hexaneand ethyl acetate, to give the title compound.

Rf value on silica gel thin layer chromatography= 0.54 (developingsolvent, hexane:ethyl acetate=2:1 by volume).

Nuclear Magnetic Resonance Spectrum (CDCl₃) δ ppm:

1.02 (3H, doublet, J=6 Hz);

1.09 (3H, doublet, J=6 Hz);

1.83 (2H, doublet, J=6 Hz);

1.8-2.3 (3H, nd);

2.11 (3H, singlet);

2.22 (3H, singlet);

2.3-2.9 (3H, nd);

2.89 (3H, singlet);

3.0-3.7 (3H, nd);

3.62 (3H, singlet);

3.92 (1H, doublet, J=4.5 Hz);

4.50 (1H, doublet, J=4.5 Hz);

4.90 (2H, singlet);

6.90 (2H, doublet, J=4.5 Hz);

8.17 (2H, doublet, J=4.5 Hz).

PREPARATION 6 (a)2-Isobutyl-6-methoxymethoxy-5,7,8-trimethyl-2-(4-nitrophenoxymethyl)chroman-4-oneand (b)6-hydroxy-2-isobutyl-5,7,8-trimethyl-2-(4-nitrophenoxymethyl)chroman-4-one(Step E7)

A mixture of 3.3 g of2-isobutyl-6-methoxymethoxy-5,7,8-trimethyl-2-(4-nitrophenoxymethyl)chromanspiro-4,2'-(1',3'-dithiane) (prepared as described in Preparation 5), 4 g ofmercuric chloride, 1.4 g of mercuric oxide and 30 ml of 10% v/v aqueousmethanol was heated under reflux for 2 hours. The reaction mixture wasthen mixed with diethyl ether, and the insoluble residue was filteredoff. The filtrate was washed with an aqueous solution of sodium chlorideand then with an aqueous solution of ammonium sulfate, and dried overanhydrous sodium sulfate. The solvent was distilled off and the residuewas purified by silica gel column chromatography eluted with a 4:1 byvolume mixture of hexane and ethyl acetate, to give the title compounds(a) and (b) separately.

Silica gel thin layer chromatography (developing solvent, hexane:ethylacetate=2:1 by volume),

(a) Rf value=0.48

(b) Rf value=0.40.

Nuclear Magnetic Resonance Spectrum (CDCl₃) δ ppm:

(a) 1.01 (6H, doublet, J=6 Hz);

1.84 (2H, singlet);

1.6-2.1 (1H, singlet);

2.12 (3H, singlet);

2.27 (3H, singlet);

2.58 (3H, singlet);

2.81 (1H, doublet, J=19 Hz);

3.00 (1H, doublet, J=19 Hz);

3.62 (3H, singlet);

4.14 (1H, doublet, J=11 Hz);

4.25 (1H, doublet, J=11 Hz);

4.89 (2H, singlet);

6.95 (2H, doublet, J=4.5 Hz);

8.20 (2H, doublet, J=4.5 Hz).

(b) 0.98 (3H, doublet, J=6 Hz);

1.00 (3H, doublet, J=6 Hz);

1.80 (2H, doublet, J=6 Hz);

1.65-2.1 (1H, nd);

2.13 (3H, singlet);

2.23 (3H, singlet);

2.57 (3H, singlet);

2.82 (1H, doublet, J=14 Hz);

3.00 (1H, doublet, J=14 Hz);

4.13 (1H, doublet, J=12 Hz);

4.27 (1H, doublet, J=12 Hz);

4.66 (1H, singlet);

6.95 (2H, doublet, J=9 Hz);

8.19 (2H, doublet, J=9 Hz).

PREPARATION 76-Acetoxy-2-isobutyl-5,7,8-trimethyl-2-(4-nitrophenoxymethyl)chroman-4-one

A mixture of 1.5 g of6-hydroxy-2-isobutyl-5,7,8-trimethyl-2-(4-nitrophenoxymethyl)chroman-4-one(prepared as described in Preparation 6) and 30 ml of pyridine was mixedwith 3 g of acetic anhydride and stirred for 35 hours at roomtemperature. The reaction mixture was then condensed by evaporationunder reduced pressure, mixed with water and extracted with ethylacetate and benzene. The extract was dried over anhydrous sodiumsulfate, and the solvent was distilled off under reduced pressure. Theresidue was purified by silica gel column chromatography, using a 5:1 byvolume mixture of hexane and ethyl acetate, to give the title compound.

Rf value on silica gel thin layer chromatography=0.42 (developingsolvent, hexane:ethyl acetate=2:1 by volume).

Nuclear Magnetic Resonance Spectrum (CDCl₃) δ ppm:

1.01 (6H, doublet, J=6 Hz);

1.7-2.2 (3H, nd);

2.09 (3H, singlet);

2.12 (3H, singlet);

2.33 (3H, singlet);

2.42 (3H, singlet);

2.91 (2H, AB type, J=18 Hz);

4.13 δ 4.25 (2H, AB type, J=9 Hz);

6.95 (2H, doublet, J=9 Hz);

8.20 (2H, doublet, J=9 Hz).

PREPARATION 86-Acetoxy-2-(4-aminophenoxymethyl)-2-isobutyl-5,7,8-trimethylchroman-4-one

1.4 g of6-acetoxy-2-isobutyl-5,7,8-trimethyl-2-(4-nitrophenoxymethyl)chroman-4-one(prepared as described in Preparation 7) was dissolved in 35 ml ofmethanol, and, in the presence of 1 g of 10% w/w palladium-on-carbon, itwas reduced for 3 hours under about 1 atmosphere (about 1 bar) pressureof hydrogen. The catalyst was filtered off, and the solvent was thendistilled off under reduced pressure to give the title compound.

Rf value on silica gel thin layer chromatography=0.54 (developingsolvent, ethyl acetate).

Nuclear magnetic Resonance Spectrum (CDCl₃) δ ppm:

0.97 (6H, doublet, J=6 Hz);

1.6-2.2 (3H, nd);

2.08 (3H, singlet);

2.14 (3H, singlet);

2.32 (3H, singlet);

2.42 (3H, singlet);

2.74 δ 3.02 (2H, AB type, J=16 Hz);

3.2 -3.7 (2H, broad singlet);

3.94 δ 4.06 (2H, AB type, J=9 Hz);

6.58 (2H, doublet, J=9 Hz);

6.73 (2H, doublet, J=9 Hz).

PREPARATION 9 Ethyl3-[4-(6-acetoxy-2-isobutyl-5,7,8-trimethyl-4-oxochroman-2-ylmethoxy)phenyl]-2-chloropropionate(Step D3)

1.5 ml of concentrated hydrochloric acid was added to mixture of 1.1 gof6-acetoxy-2-(4-aminophenoxymethyl)-2-isobutyl-5,7,8-trimethylchroman-4-one(prepared as described in Preparation 8) and 20 ml of acetone under anitrogen stream and at room temperature. This was followed by 0.8 g ofsodium nitrite and 0.3 ml of water, and then by 4 g of ethyl acrylate.0.1 g of cuprous oxide was added at room temperature to the reactionmixture, which was then stirred for 1 hour. Water was then added, andthe mixture was extracted with benzene. The benzene extract was washedwith water and dried over anhdyrous sodium sulfate, and the solvent wasdistilled off under reduced pressure. The residue was purified by silicagel column chromatography using a 5.1 by volume mixture of hexane andethyl acetate as eluent, to give the title compound.

Rf value on silica gel thin layer chromatography=0.74 (developingsolvent, hexane:ethyl acetate=1:2 by volume).

Nuclear magnetic Resonance Spectrum (CDCl₃) δ ppm:

0.98 (6H, doublet, J=6 Hz);

1.25 (3H, triplet, J=7 Hz);

1.5-2.2 (3H, nd);

2.08 (3H, singlet);

2.13 (3H, singlet);

2.32 (3H, singlet);

2.42 (3H, singlet);

2.78 δ 3.01 (2H, AB type, J=17 Hz);

2.8-3.5 (2H, nd);

3.8-4.5 (5H, nd);

6.82 (2H, doublet, J=9 Hz);

7.11 (2H, doublet, J=9 Hz).

PREPARATION 10 Ethyl 6-hydroxy-5,7,8-trimethylchroman-2-carboxylate(Step C4)

14 g of ethyl 6-hydroxy-5,7,8-trimethyl-4-oxo-2H-chromene-2-carboxylate[prepared as described in J. Med. Chem., 18, 934 (1975)] were dissolvedin 320 ml of acetic acid, and the resulting solution was catalyticallyreduced for 1 hour at 60°-65° C., under a hydrogen pressure of 3atmospheres and in the presence of 3.5 g of 10% w/w palladium-on-carbon.The catalyst was filtered off, and the filtrate was poured into water.The white crystals which separated were collected by filtration, to givethe title compound, melting at 108°-109° C.

Nuclear Magnetic Resonance Spectrum (CDCl₃) δ ppm:

1.28 (3H, triplet, J=7 Hz);

2.07 (3H, singlet);

2.17 (6H, singlet);

1.9-2.3 (2H, nd);

2.65 (2H, broad triplet, J=7 Hz);

4.22 (2h, broad triplet, J=7 hz);

4.1-4.3 (1H, nd);

4.60 (1H, doublet of doublets, J=7 δ 4 Hz).

PREPARATION 11 Ethyl6-methoxymethoxy-5,7,8-trimethylchroman-2-carboxylate (Step C5)

3 g of a 55% w/w suspension of sodium hydride in mineral oil were washedtwice with cyclohexane. A mixture of 14.3 g of ethyl6-hydroxy-5,7,8-trimethylchroman-2-carboxylate (prepared as described inPreparation 10) and 130 ml of dimethylformamide was added slowly to thissuspension under a nitrogen stream at 5°-10° C. The reaction mixture wasstirred for 1 hour, and then cooled in ice to 3°-5° C., after which 5.6g of chloromethyl methyl ether were added dropwise. After this addition,the reaction mixture was stirred for 1 hour at room temperature, pouredinto ice-water, and then extracted with cyclohexane. The cyclohexaneextract was washed with water and dried over anhydrous sodium sulfate.The solvent was then distilled off under reduced pressure. The residuewas purified by silica gel column chromatography using a 25:1 by volumemixture of benzene and ethyl acetate as eluent, to give the titlecompound.

Rf value on silica gel thin layer chromatography=0.41 (developingsolvent, benzene:ethyl acetate=20:1 by volume).

Nuclear Magnetic Resonance Spectrum (CDCl₃) δ ppm:

1.27 (3H, triplet, J=7 Hz);

2.0-2.4 (2H, nd);

2.15 (3H, singlet);

2.16 (3H, singlet);

2.2 (3H, singlet);

2.64 (2H, broad triplet, J=7 Hz);

3.61 (3H, singlet);

4.24 (2H, quartet, J=7 Hz);

b 4.64 (1H, doublet of doublets, J=4 δ 7 Hz);

4.87 (2H, singlet).

PREPARATION 12 Ethyl6-methoxymethoxy-5,7,8-trimethyl-2-octylchroman-2-carboxylate (Step C6)

7.8 ml of a hexane solution containing 1.62 mmole/ml of butyllithiumwere added dropwise to a mixture of 2 g of diisopropylamine and 80 ml oftetrahydrofuran under a nitrogen stream at a temperature from -60° to-50° C. The resulting mixture was then allowed to stand for 10 minutesat room temperature, after which about 10 ml of tetrahydrofurancontaining 4 g of ethyl6-methoxymethoxy-5,7,8-trimethylchroman-2-carboxylate (prepared asdescribed in Preparation 11) were added and the mixture was stirred for1 hour at -60° C. About 20 ml of tetrahydrofuran containing 5 g of octylbromide were added, and the mixture was stirred for 1 hour at -60° C.and then for 1 hour at room temperature, after which it was heated for 1hour at 50° C. The reaction mixture was then poured into ice-water andextracted with ethyl acetate. The extract was washed with water anddried over anhydrous sodium sulfate. The solvent was removed bydistillation under reduced pressure, and the residue was subjected tosilica gel column chromatography eluted with benzene, to give the titlecompound.

Rf value on silica gel thin layer chromatography=0.58 (developingsolvent, benzene:ethyl acetate=20:1 by volume).

Nuclear Magnetic Resonance Spectrum (CDCl₃) δ ppm:

0.89 (3H, broad triplet, J=6 Hz);

1.15 (3H, triplet, J=7 Hz);

1.2-1.6 (12H, multiplet);

1.6-2.4 (4H, multiplet);

2.1 (3H, singlet);

2.18 (3H, singlet);

2.2 (3H, singlet);

2.4-2.7 (2H, multiplet);

3.59 (3H, singlet);

4.11 (2H, quartet, J=7 Hz);

4.85 (2H, singlet).

PREPARATION 136-Methoxymethoxy-5,7,8-trimethyl-2-octylchroman-2-yl-methanol (Step A1')

10 ml of tetrahydrofuran containing 3.3 g of ethyl6-methoxymethoxy-5,7,8-trimethyl-2-octylchroman-2-carboxylate (preparedas described in Preparation 12) were added dropwise to a mixture of 0.45g of lithium aluminum hydride and 30 ml of tetrahydrofuran under anitrogen stream, and whilst ice-cooling. The resulting mixture wasstirred for 3 hours at room temperature. Ethyl acetate and 5% w/vaqueous hydrochloric acid were then added to the reaction mixture,whilst ice-cooling, and the organic layer was separated. Then theaqueous layer was extracted with ethyl acetate. The organic layer andthe extract were combined, washed with a saturated aqueous solution ofsodium chloride and dried over anhydrous sodium sulfate. The solvent wasremoved by distillation under reduced pressure, to give the titlecompound.

Rf value on silica gel thin layer chromatography=0.45 (developingsolvent, benzene:ethyl acetate=10.1 by volume).

Nuclear magnetic Resonance Spectrum (CDCl₃) δ ppm:

0.7-1.0 (3H, multiplet);

1.0-2.3 (16H, multiplet);

2.10 (3H, singlet);

2.15 (3H, singlet);

2.20 (3H, singlet);

2.59 (2H, broad triplet, J=7 Hz);

3.6 (5H, singlet);

4.87 (2H, singlet).

PREPARATION 146-Methoxymethoxy-5,7,8-trimethyl-2-(4-nitrophenoxymethyl)-2-octylchroman(Step A2)

0.38 g of a 55% w/w suspension of sodium hydride in mineral oil wasadded to a mixture of 3 g of6-methoxymethoxy-5,7,8-trimethyl-2-octylchroman-2-ylmethanol (preparedas described in Preparation 13) and 25 ml of dimethylformamide under anitrogen stream at room temperature, and the resulting mixture washeated for 2 hours at 50° C. A mixture of 1.4 g of p-chloronitrobenzeneand 2 ml of benzene was then added dropwise, whilst ice-cooling, and theresulting mixture was heated for 2 hours at 50° C. The reaction mixturewas then poured into ice-water and extracted with benzene. The extractwas washed with water and dried over anhydrous sodium sulfate. Thesolvent was removed by distillation under reduced pressure, and theresidue was purified by silica gel column chromatography eluted withbenzene, to give the title compound.

Rf value on silica gel thin layer chromatography=0.46 (developingsolvent, benzene).

Nuclear Magnetic Resonance Spectrum (CDCl₃) δ ppm:

0.7-1.0 (3H, multiplet);

1.0-1.9 (14H, multiplet);

1.9-2.3 (2H, nd);

2.06 (3H, singlet);

2.15 (3H, singlet);

2.19 (3H, singlet);

2.6 (2H, broad triplet, J=7 Hz);

3.60 (3H, singlet);

4.05 (2H, singlet);

4.87 (2H, singlet);

6.97 (2H, doublet, J=9 Hz);

8.18 (2H, doublet, J=9 Hz).

PREPARATION 156-Hydroxy-5,7,8-trimethyl-2-(4-nitrophenoxymethyl)-2-octylchroman (StepA3, Deprotection)

A mixture of 3.7 g of6-methoxymethoxy-5,7,8-trimethyl-2-(4-nitrophenoxymethyl)-2-octylchroman(prepared as described in Preparation 14), 10 ml of acetic acid, 30 mlof benzene and 0.75 ml of 10% w/v aqueous sulfuric acid was heated underreflux for 30 minutes. The reaction mixture was then poured into waterand extracted with benzene. The extract was washed with water and driedover anhydrous sodium sulfate. The solvent was removed by distillationunder reduced pressure, to give the title compound.

Rf value on silica gel thin layer chromatography=0.34 (developingsolvent, benzene).

Nuclear magnetic Resonance Spectrum (CDCl₃) δ ppm:

0.7-1.0 (3H, multiplet);

1.0-1.85 (14H, multiplet);

1.85-2.2 (2H, nd);

2.10 (6H, singlet);

2.16 (3H, singlet);

2.63 (2H, broad triplet, J=7 Hz);

4.06 (2H, singlet);

4.19 (1H, singlet, disappeared on adding heavy water);

6.97 (2H, doublet, J=9 Hz);

8.19 (2H, doublet, J=9 Hz).

PREPARATION 166-Acetoxy-5,7,8-trimethyl-2-(4-nitrophenoxymethyl)-2-octylchroman (StepA3, Acylation)

1.2 g of acetic anhydride was added to a mixture of 3.5 g of6-hydroxy-5,7,8-trimethyl-2-(4-nitrophenoxymethyl)-2-octylchroman(prepared as described in Preparation 15), 10 ml of pyridine and 10 mlof benzene, and the mixture was stirred for 2hours at room temperature.The reaction mixture was then poured into water and extracted withbenzene. The extract was washed with 5% w/v aqueous hydrochloric acidand water, successively in that order, and dried over anhydrous sodiumsulfate. The solvent was removed by distillation under reduced pressure,to give the title compound.

Rf value on silica gel thin layer chromatography=0.4 (developingsolvent, benzene).

Nuclear Magnetic Resonance Spectrum (CDCl₃) δ ppm:

0.75-1.0 (3H, multiplet);

1.1-1.65 (12H, multiplet);

1.65-2.15 (4H, nd);

1.99 (3H, singlet);

2.04 (3H, singlet);

2.08 (3H, singlet);

2.32 (3H, singlet);

2.63 (2H, broad triplet, J=7 Hz);

4.07 (2H, singlet);

6.98 (2H, doublet, J=9 Hz);

8.20 (2H, doublet, J=9 Hz).

PREPARATION 176-Acetoxy-2-(4-aminophenoxymethyl)-5,7,8-trimethyl-2-octylchroman (StepA3, Hydrogenation)

Using Paar's hydrogenation apparatus, a mixture of 4 g of6-acetoxy-5,7,8-trimethyl-2-(4-nitrophenoxymethyl)-2-octylchroman(prepared as described in Preparation 16), 0.8 g of 10% w/wpalladium-on-carbon, 30 ml of methanol and 10 ml of benzene was stirredfor 5 hours under 3-5 atmospheres (about 3-5 bars) pressure or hydrogen.The catalyst was filtered off, and the filtrate was condensed byevaporation under reduced pressure. The crystals thus obtained werewashed with hexane to give the title compound, melting at 112°-114° C.

Nuclear Magnetic Resonance Spectrum (CDCl₃) δ ppm:

0.7-1.05 (3H, multiplet);

1.05-1.65 (12H, multiplet);

1.65-2.2 (4H, nd);

1.97 (3H, singlet);

2.02 (3H, singlet);

2.10 (3H, singlet);

2.31 (3H, singlet);

2.59 (2H, broad triplet, J=7 Hz);

3.0-3.7 (2H, broad singlet, disappeared on adding heavy water);

3.86 (2H, singlet);

6.62 (2H, doublet, J=10 Hz);

6.75 (2H, doublet, J=10 Hz).

PREPARATION 18 Ethyl30[4-(6-acetoxy-5,7,8-trimethyl-2-octylchroman-2-ylmethoxy)phenyl]-2-chloropropionate(Step A4)

3.5 ml of concentrated hydrochloric acid, 1.7 ml of water containing0.61 g of sodium nitrite and 7.2 ml of ethyl acrylate were addeddropwise successively, in that order, under a nitrogen stream and at5°-10° C., to a mixture of 3.2 g of6-acetoxy-2-(4-aminophenoxy-methyl)-5,7,8-trimethyl-2-octylchroman(prepared as described in Preparation 17) and 35 ml of acetone. Thereaction mixture was then heated to 40°-43° C. (inner temperature), and0.1 g of cuprous oxide was slowly added. After about 30 minutes,nitrogen generation ceased. The reaction mixture was then poured intowater and extracted with benzene. The extract was washed with water anddried over anhydrous sodium sulfate. The solvent was removed bydistillation under reduced pressure. The residue was purified by silicagel column chromatography using a 10:1 by volume mixture of cyclohexaneand ethyl acetate as eluent, to give the title compound.

Rf value on silica gel thin layer chromatography=0.27 (developingsolvent, cyclohexane:ethyl acetate=9:1 by volume).

Nuclear Magnetic Resonance Spectrum (CDCl₃) δ ppm:

0.8-1.05 (3H, multiplet);

1.05-1.65 (15H, multiplet);

1.65-2.2 (4H, nd);

1.97 (3H, singlet);

2.03 (3H, singlet);

2.09 (3H, singlet);

2.30 (3H, singlet);

2.6 (2H, broad triplet, J=7 Hz);

3.07 (1H, doublet of doublets, J=7 δ 14 Hz);

3.30 (1H, doublet of doublets, J=7 δ 14 Hz);

3.92 (2H, singlet);

4.18 (2H, quartet, J=7 Hz);

4.36 (1H, triplet, J=7 Hz);

6.85 (2H, doublet, J=9 Hz);

7.13 (2H, doublet, J=9 Hz).

PREPARATION 196-Acetoxy-2-methyl-2-(4-nitrophenoxymethyl)-7-(1,1,3,3-tetramethylbutyl)chroman-4-one(Step D1)

A mixture of 23 g of5-acetoxy-2-hydroxy-4-(1,1,3,3-tetramethylbutyl)acetophenone, 14.7 g of1-(4-nitrophenoxy)-2-propanone, 8 g of pyrrolidine and 300 ml of benzenewas stirred for 3 hours at room temperature, and then heated underreflux for 10 hours. The reaction mixture was then poured into ice-waterand extracted with benzene. The extract was washed with 5% w/v aqueoushydrochloric acid and water successively in that order, and then driedover anhydrous sodium sulfate. The solvent was removed by distillationunder reduced pressure. The residue was mixed with 15 g of aceticanhydride and 400 ml of pyridine, and the mixture was allowed to standfor 1 day at room temperature. The reaction mixture was then poured intoice-water and extracted with benzene. The extract was washed with 5% w/vaqueous hydrochloric acid and water in that order, and then dried overanhydrous sodium sulfate. The solvent was removed by distillation underreduced pressure. The residue was purified by silica gel columnchromatography, eluted with a 20:1 by volume mixture of benzene andethyl acetate, and recrystallized from methanol, to give the titlecompound, melting at 165.5°-167° C.

Nuclear Magnetic Resonance Spectrum (CDCl₃) δ ppm:

0.76 (9H, singlet);

1.36 (6H, singlet);

1.57 (3H, singlet);

1.83 (2H, singlet);

2.32 (3H, singlet);

2.74 (1H, doublet, J=17 Hz);

3.10 (1H, doublet, J=17 Hz);

4.11 δ 4.24 (2H, AB type, J=9 Hz);

6.95 (2H, doublet J=9 Hz);

6.98 (1H, singlet);

7.50 (1H, singlet);

8.20 (2H, doublet, J=9 Hz).

PREPARATION 206-Acetoxy-4-hydroxy-2-methyl-2-(4-nitrophenoxymethyl)-7-(1,1,3,3-tetramethylbutyl)chroman(Step F1)

1 g of sodium borohydride was added, whilst ice-cooling, to a mixture of100 ml of methanol and 10 ml of benzene containing 13 g of6-acetoxy-2-methyl-2-(4-nitrophenoxymethyl)-7-(1,1,3,3-tetramethylbutyl)chroman-4-one(prepared as described in Preparation 19), and the mixture was stirredfor 30 minutes whilst ice-cooling. The reaction mixture was then pouredinto ice-water, neutralized with 10% w/v aqueous hydrochloric acid andextracted with benzene. The extract was washed with water and dried overanhydrous sodium sulfate. The solvent was removed by distillation underreduced pressure. The residue was purified by silica gel columnchromatography, eluted with a 4:1 by volume mixture of benzene and ethylacetate, to give the title compound.

Rf value on silica gel thin layer chromatography=0.32 (developingsolvent, benzene:ethyl acetate=4:1 by volume).

Nuclear Magnetic Resonance Spectrum (CDCl₃) δ ppm:

0.77 (9H, singlet);

1.34 (6H, singlet);

1.54 (3H, singlet);

1.80 (2H, singlet);

1.85-2.25 (1H, nd);

2.29 (3H, singlet);

2.48 (1H, doublet of doublets, J=7 δ 14 Hz);

4.02 (2H, AB type, J=12 Hz);

4.7-5.0 (1H, multiplet);

6.85 (1H, singlet);

6.95 (2H, doublet, J=9 Hz);

7.08 (1H, singlet);

8.18 (2H, doublet, J=9 Hz).

PREPARATION 21 (a)6-Hydroxy-2-methyl-2-(4-nitrophenoxymethyl)-7-(1,1,3,3-tetramethylbutyl)-2H-chromeneand (b)6-Acetoxy-2-methyl-2-(4-nitrophenoxymethyl)-7-(1,1,3,3-tetramethylbutyl)-2H-chromene(Step F3)

A solution of 10.2 g of6-acetoxy-4-hydroxy-2-methyl-2-(4-nitrophenoxymethyl)-7-(1,1,3,3-tetramethylbutyl)chroman(prepared as described in Preparation 20) and 0.4 g of p-toluenesulfonicacid in 200 ml of benzene was heated under reflux for 30 minutes under anitrogen stream. The reaction mixture was then poured into ice-water andextracted with benzene. The extract was washed with water and dried overanhydrous sodium sulfate. The solvent was removed by distillation underreduced pressure. The residue was purified by silica gel columnchromatography, eluted with benzene, to give the title compounds (a) and(b).

Rf value on silica gel thin layer chromatography (developing solvent,benzene:ethyl acetate=20:1 by volume)=0.53 and 0.50, respectively.

Nuclear Magnetic Resonance Spectrum (a) (CDCl₃) δ ppm:

0.75 (9H, singlet);

1.38 (6H, singlet);

1.56 (3H, singlet);

1.89 (2H, singlet);

4.09 (2H, singlet);

4.43 (1H, singlet, disappeared on adding heavy water);

5.63 (1H, doublet, J=10 Hz);

6.32 (1H, singlet);

6.41 (1H, doublet, J=10 Hz);

6.73 (1H, singlet);

6.96 (2H, doublet, J=9 Hz);

8.20 (2H, doublet, J=9 Hz).

Nuclear Magnetic Resonance Spectrum (b) (CDCl₃) δ ppm:

0.76 (9H, singlet);

1.32 (6H, singlet);

1.58 (3H, singlet);

1.79 (2H, singlet);

2.29 (3H, singlet);

4.10 (2H, singlet);

5.62 (1H, doublet, J=10 Hz);

6.43 (1H, doublet, J=10 Hz);

6.69 (1H, singlet);

6.79 (1H, singlet);

6.93 (2H, doublet, J=9 Hz);

8.18 (2h, doublet, J=9 Hz).

PREPARATION 226-Acetoxy-2-(4-aminophenoxymethyl)-2-methyl-7-(1,1,3,3-tetramethylbutyl)chroman(Step F5)

Using Paar's hydrogenation apparatus, a mixture of 9.1 g of6-acetoxy-2-methyl-2-(4-nitrophenoxymethyl)-7-(1,1,3,3-tetramethylbutyl)-2H-chromene(prepared as described in Preparation 21), 2g of 10% w/wpalladium-on-carbon and 150 ml of methanol was stirred for 10 hoursunder 3-5 atmospheres (about 3-5-bars) pressure of hydrogen. Thecatalyst was filtered off, and the filtrate was condensed by evaporationunder reduced pressure. The residue was purified by silica gel columnchromatography, eluted with a 10:1 by volume mixture of benzene andethyl acetate, to give the title compound.

Rf value on silica gel thin layer chromatography=0.27 (developingsolvent, benzene:ethyl acetate=9:1 by volume).

Nuclear Magnetic Resonance Spectrum (CDCl₃) δ ppm:

0.77 (9H, singlet);

1.34 (6H, singlet);

1.42 (3H, singlet);

1.7-2.2 (2H, nd);

1.78 (2H, singlet);

2.27 (3H, singlet);

2.65 (2H, broad quartet, J=7 Hz);

3.36 (2H, broad singlet, disappeared on adding heavy water);

3.85 (2H, AB type J9 Hz);

6.54-6.88 (6H, multiplet).

PREPARATION 23 Ethyl3-{4-[6-acetoxy-2-methyl-7-(1,1,3,3-tetramethylbutyl)chroman-2-ylmethoxy]phenyl{-2-chloropropionate(Step A4)

Following the same procedure as described in Preparation 18, 7.9 g of6-acetoxy-2-(4-aminophenoxymethyl)-2-methyl-7-(1,1,3,3-tetramethylbutyl)chroman (prepared as described in Preparation 22), 1.6 g of sodiumnitrite, 9 ml of concentrated hydrochloric acid, 18 g of ethyl acrylate,260 mg of cuprous oxide, 90 ml of acetone and about 5 ml of water werereacted, to give the title compound.

Rf value on silica gel thin layer chromatography=0.55 (developingsolvent, benzene:ethyl acetate=20:1 by volume).

Nuclear Magnetic Resonance Spectrum (CDCl₃) δ ppm:

0.78 (9H, singlet);

1.22 (3H, triplet, J=7 Hz);

1.35 (6H, singlet);

1.43 (3H, singlet);

1.7-2.3 (2H, nd);

1.79 (2H, singlet);

2.27 (3H, singlet);

2.70 (2H, broad triplet, J=6 Hz);

3.07 (1H, doublet of doublets, J=7.5 δ 15 Hz);

3.32 (1H, doublet of doublets, J=7.5 δ 15 Hz);

3.91 (2H, AB type, J=9 Hz);

4.18 (2H, quartet, J=7 Hz);

4.37 (1H, triplet, J=7 Hz);

6.72 (1H, singlet);

6.85 (1H, singlet);

6.86 (2H, doublet, J=9 Hz);

7.16 (2H, doublet, J=9 Hz).

PREPARATION 246-Acetoxy-2-(4-aminophenoxymethyl)-2-methyl-4-oxo-7-(1,1,3,3-tetramethylbutyl)chroman(Step D2)

12.3 g of6-acetoxy-2-methyl-2-(4-nitrophenoxymethyl)-7-(1,1,3,3-tetramethylbutyl)chroman-4-one(prepared as described in Preparation 19) were dissolved in a mixture of200 ml of methanol and 20 ml of benzene, and then catalytically reducedfor 6 hours at room temperature, in the presence of 2.4 g of 10% w/wpalladium-on-carbon, under 1 atmosphere (about 1 bar) pressure ofhydrogen. The catalyst was filtered off, and the filtrate was condensedby evaporation under reduced pressure. The residue was purified bysilica gel column chromatography, eluted with a 4:1 by volume mixture ofbenzene and ethyl acetate, to give the title compound.

Rf value on silica gel thin layer chromatography =0.29 (developingsolvent, benzene:ethyl=4:1 by volume).

Nuclear Magnetic Resonance Spectrum (CDCl₃) δ ppm:

0.78 (9H, singlet);

1.37 (6H, singlet);

1.52 (3H, singlet);

1.83 (2H, singlet);

2.30 (3H, singlet);

2.66 (1H, doublet, J=17 Hz);

3.10 (1H, doublet, J=17 Hz);

3.4 (2H, broad singlet, disappeared on adding heavy water);

3.92 δ 4.06 (2H, AB type, J=9 Hz);

6.58 (2H, doublet, J=9 Hz);

6.76 (2H, doublet, J=9 Hz);

7.00 (1H, singlet);

7.50 (1H, singlet).

PREPARATION 25 Ethyl3-{4-[6-acetoxy-2-methyl-4-oxo-7-(1,1,3,3-tetramethylbutyl)chroman-2-ylmethoxy]phenyl}-2-chloropropionate (Step D3)

Following the same procedure as described in Preparation 18, 9 g of6-acetoxy-2-(4-aminophenoxymethyl)-2-methyl-7-(1,1,3,3-tetramethylbutyl)chroman-4-one (prepared as described in Preparation 24), 1.8 g of sodiumnitrite, 10 ml of concentrated hydrochloric acid, 20 g of ethylacrylate, 0.3 g of cuprous oxide, 100 ml of acetone and about 8 ml ofwater were reacted, to give the title compound.

Rf value on silica gel thin layer chromatography=0.32 (developingsolvent, benzene:ethyl acetate=20:1 by volume).

Nuclear Magnetic Resonance Spectrum (CDCl₃) δ ppm:

0.78 (9H, singlet);

1.23 (3H, triplet, J=7 Hz);

1.38 (6H, singlet);

1.53 (3H, singlet);

1.85 (2H, singlet);

2.30 (3H, singlet);

2.69 (1H, doublet, J=17 Hz);

3.08 (1H, doublet of doublets, J=7.5 δ 15 Hz);

3.10 (1H, doublet, J=17 Hz);

3.32 (1H, doublet of doublets, J=7.5 δ 15 Hz);

3.99 δ 4.12 (2H, AB type, J=10.5 Hz);

4.18 (2H, quartet, J=7 Hz);

4.36 (1H, triplet, J>7 Hz);

6.82 (2H, doublet, J=9 Hz);

7.01 (1H, singlet);

7.16 (2H, doublet, J=9 Hz);

7.52 (1H, singlet).

PREPARATION 265-{4-[6-Acetoxy-2-methyl-4-oxo-7-(1,1,3,3-tetramethylbutyl)chroman-2-ylmethoxy]benzyl}-2-iminothiazolidin-4-one

After completing the silica gel column chromatography described inExample 6, the column was further eluted with a 4:1 by volume mixture ofbenzene and tetrahydrofuran, to give the title compound melting at125°-130° C.

Nuclear magnetic Resonance Spectrum [(CD₃)₂ CO] δppm:

0.77 (9H, singlet);

1.39 (6H, singlet);

1.53 (3H, singlet);

1.89 (2H, singlet);

2.34 (3H, singlet);

2.6-3.0 (1H, nd);

2.75 (1H, doublet, J=16 Hz);

3.13 (1H, doublet, J=16 Hz);

3.40 (1H, doublet of doublets, J=4 δ 14 Hz);

4.17 (2H, singlet);

4.48 (1H, doublet of doublets, J=4 δ 10 Hz);

6.87 (2H, doublet, J=9 Hz);

7.01 (1H, singlet);

7.20 (2H, doublet, J=9 Hz);

7.46 (1H, singlet);

7.8-8.7 (2H, broad, disappeared on adding heavy water.

PREPARATION 27 Ethyl2-(3,7-dimethyloctyl)-6-methoxymethoxy-5,7,8-trimethylchromanspiro-4,2'-(1',3-dithiane) -2-carboxylate (Step E4)

17.7 ml of a hexane solution containing 1.62 mmole/ml of butyllithiumwere added dropwise under a nitrogen stream at a temperature between-60° C. and -50° C. to a solution of 2.9 g of diisopropylamine in 30 mlof tetrahydrofuran, and the mixture was allowed to stand for 10 minutesat room temperature. 10 ml of tetrahydrofuran containing 6 g of ethyl6-methoxymethoxy-5,7,8-trimethylchromanspiro-4,2'-(1',3'-dithiane)-2-carboxylate(prepared as described in Preparation 3) were added dropwise to thereaction mixture at -60° C. The reaction mixture was stirred for 1 hour,and then 5 ml of tetrahydrofuran containing 6.4 g of 3,7-dimethyloctylbromide were added dropwise, and the mixture was stirred for a further 1hour at the same temperature. After the mixture had been stirred for afurther 1 hour at room temperature and then stirred for 1.5 hours at45°-50° C., the resulting mixture was allowed to stand overnight at roomtemperature. The reaction mixture was then poured into ice-water andextracted with ethyl acetate. The extract was washed with a saturatedaqueous solution of sodium chloride and dried over anhydrous sodiumsulfate. The solvent was removed by distillation under reduced pressure.The residue was purified by silica gel column chromatography, elutedwith a 10:1 by volume mixture of hexane and ethyl acetate, to give thetitle compound as a pale yellow oily substance.

Rf value on silica gel thin layer chromatography=0.57 (developingsolvent, benzene:ethyl acetate=20:1 by volume).

Nuclear magnetic Resonance Spectrum (CDCl₃) δ ppm:

0.87 (9H, doublet, J=7 Hz);

1.0-2.3 (14H, multiplet);

1.17 (3H, triplet, J=7 Hz);

2.17 (3H, singlet);

2.21 (3H, singlet);

2.3-2.9 (2H, nd);

2.62 (1H, doublet, J=14 Hz);

2.83 (3H, singlet);

2.97-3.5 (2H, multiplet);

3.59 (3H, singlet);

3.73 (1H, doublet, J=14 Hz);

4.03 (1H, quarter, J=7 Hz);

4.07 (1H, quartet, J=7 Hz);

4.88 (2H, singlet).

PREPARATION 282-(3,7-Dimethyloctyl)-2-hydroxymethyl-6-methoxymethoxy-5,7,8-trimethylchromanspiro-4,2'-(1',3'-dithiane)(Step E5)

20 ml of tetrahydrofuran containing 4 g of ethyl2-(3,7-dimethyloctyl)-6-methoxymethoxy-5,7,8-trimethylchromanspiro-4,2'-(1'3'-dithiane)-2-carboxylate(prepared as described in Preparation 27) were added dropwise under anitrogen stream and whilst ice-cooling to a mixture of 0.41 g of lithiumaluminum hydride and 30 ml of tetrahydrofuran, and the mixture was thenstirred for 3 hours at room temperature. About 10 ml of ethyl acetateand about 30 ml of 5% w/v aqueous hydrochloric acid were then added, andthe organic layer was separated. The aqueous layer was further extractedwith ethyl acetate. The organic layer and the ethyl acetate extract werecombined and washed with a saturated aqueous solution of sodium chlorideand then dried over anhydrous sodium sulfate. The solvent was removed bydistillation under reduced pressure to give the title compound as a paleyellow oil.

Rf value on silica gel thin layer chromatography=0.36 (developingsolvent, benzene:ethyl acetate=20.1 by volume).

Nuclear magnetic Resonance Spectrum (CDCl₃) δ ppm:

0.87 (9H, doublet, J=7 Hz);

1.0-2.0 (12H, multiplet);

3.0-2.5 (2H, nd);

2.08 (3H, singlet);

2.20 (3, singlet);

2.34 (1H, broad singlet, disappeared on adding heavy water);

2.5-3.0 (3H, multiplet);

2.92 (3H, singlet);

3.0-3.6 (4H, multiplet);

3.61 (3H, singlet); 3.76 (1H, doublet of doublets, J=6 & 12 Hz); 4.89(2H, singlet).

PREPARATION 292-(3,7-Dimethyloctyl)-6-methoxymethoxy-5,7,8-trimethyl-2-(4-nitrophenoxymethyl)chromanspiro-4,2'-(1',3'-dithiane)(Step E6)

0.46 g of a 55% w/w suspension of sodium hydride in mineral oil wereadded to a mixture of 3.6 g of2-(3,7-dimethyloctyl)-2-hydroxymethyl-6-methoxymethoxy-5,7,8-trimethylchromanspiro-4,2'-(1',3'-dithiane)(prepared as described in Preparation 28) and 30 ml of dimethylformamideunder a nitrogen stream at room temperature, and the resulting mixturewas heated at 50° C. for 2 hours. A mixture of 1.66 g ofp-chloronitrobenzene and 3 ml of benzene was added dropwise, and thenthe mixture was heated at 50° C. for 2 hours. The reaction mixture wasthen poured into water and extracted with benzene. The extract waswashed with water and dried over anhydrous sodium sulfate. The solventwas distilled off under reduced pressure. The residue was purified bysilica gel column chromatography, eluted with a 50:1 by volume mixtureof benzene and ethyl acetate, to give the title compound.

Rf value on silica gel thin layer chromatography=0.55 (developingsolvent, benzene:ethyl acetate=20:1 by volume).

Nuclear Magnetic Resonance Spectrum (CDCl₃) δ ppm: 0.87 (9H doublet, J=7Hz); 1.0-2.3 (14H, multiplet); 2.08 (3H, singlet); 2.21 (3H, singlet);2.3-3.0 (3H, multiplet); 2.89 (3H, singlet); 3.0-3.6 (3H, multiplet);3.61 (3H, singlet); 3.99 (1H, doublet, J=9 Hz); 4.45 (1H, doublet, J=9Hz); 4.89 (2H, singlet); 6.92 (2H, doublet, J=9 Hz); 8.17 (2H, doublet,J=9 Hz).

PREPARATION 302-(3,7-Dimethyloctyl)-6-hydroxy-5,7,8-trimethyl-2-(4-nitrophenoxymethyl)chroman-4-one(Steps E7 and A3, Deprotection)

A mixture of 3.4 g of2-(3,7-dimethyloctyl)-6-methoxymethoxy-5,7,8-trimethyl-2-(4-nitrophenoxymethyl)chromanspiro-4,2'-(1',3'-dithiane)(prepared as described in Preparation 29), 2.2 g of mercuric chloride,1.7 g of mercuric oxide, 10 ml of tetrahydrofuran, 27 ml of methanol and3 ml of water was heated under reflux for 2 hours. Benzene was thenadded to the reaction mixture, and the insoluble residue was filteredoff. The filtrate was washed with an aqueous ammonium sulfate solution,and then with water, and dried over anhydrous sodium sulfate. Thesolvent was distilled off under reduced pressure. 30 ml of benzene, 10ml of acetic acid and 0.5 ml of 10% w/v aqueous sulfuric acid was addedto the residue, and the mixture was heated under reflux for 30 minutes.The reaction mixture was then poured into water and extracted withbenzene. The extract was washed with water and dried over anhydroussodium sulfate. The solvent was distilled off under reduced pressure.The residue was subjected to silica gel column chromatography, elutedwith a 100:3 by volume mixture of benzene and ethyl acetate, and theresulting crystals were recrystallized from a mixture of benzene andhexane to give the title compound, melting at 121°-123° C.

Nuclear Magnetic Resonance Spectrum (CDCl₃) δ ppm: 0.85 (9H, doublet,J=7 Hz); 1.0-1.7 (10H, multiplet); 1.7-2.1 (2H, multiplet); 2.11 (3H,singlet); 2.21 (3H, singlet); 2.55 (3H, singlet); 2.76 & 2.98 (2H, ABtype, J=16 Hz); 4.16 (2H, singlet); 4.57 (1H, singlet, disappeared onadding heavy water); 7.96 (2H, doublet, J=9 Hz); 8.20 (2H, doublet, J=9Hz);

PREPARATION 31 6-Acetoxy-2-(3,7-dimethyloctyl)-5,7,8-trimethyl-2-(4-nitrophenoxymethyl)chroman-4-one(Step A3, Acylation)

Following the same procedure as described in Preparation 16, 1.8 g of2-(3,7-dimethyloctyl)-6-hydroxy-5,7,8-trimethyl-2-(4-nitrophenoxymethyl)chroman-4-one(prepared as described in Preparation 30), 0.5 g of acetic anhydride, 5ml of pyridine and 10 ml of benzene were reacted, to give the titlecompound.

Rf value on silica gel thin layer chromatography=0.41 (developingsolvent, benzene:ethyl acetate=20:1 by volume).

Nuclear Magnetic Resonance Spectrum (CDCl₃) δ ppm: 0.85 (9H, doublet,J=7 Hz); 1.0-2.0 (12H, multiplet); 2.08 (3H, singlet); 2.11 (3H,singlet); 2.33 (3H, singlet); 2.41 (3H, singlet); 2.80 & 3.00 (2H, ABtype, J=16 Hz); 4.17 (2H, singlet); 6.95 (2H, doublet, J=9 Hz); 8.20(2H, doublet, J=9 Hz).

PREPARATION 326-Acetoxy-2-(4-aminophenoxymethyl)-2-(3,7-dimethyloctyl-5,7,8-trimethylchroman-4-one(Step D2)

Following the same procedure as described in Preparation 24, 1.95 g of6-acetoxy-2-(3,7-dimethyloctyl)-5,7,8-trimethyl-2-(4-nitrophenoxymethyl)chroman-4-one(prepared as described in Preparation 31) were treated with 0.4 g of 10%w/w palladium-on-carbon, to give the title compound.

Rf value on silica gel thin layer chromatography=0.31 (developingsolvent, benzene:ethyl acetate=4:1 by volume).

Nuclear Magnetic Resonance Spectrum (CDCl₃) δ ppm: 0.85 (9H, doublet,J=7 Hz); 1.0-2.0 (12H, multiplet); 2.09 (3H, singlet); 2.13 (3H,singlet); 2.32 (3H, singlet); 2.41 (3H, singlet); 2.77 & 3.00 (2H, ABtype, J=16 Hz); 3.4 (2H, broad singlet, disappeared on adding heavywater); 3.99 (2H, singlet); 6.60 (2H, doublet, J=9 Hz); 6.70 (2H,doublet, J=9 Hz).

PREPARATION 33 Ethyl3-{4-[6-acetoxy-2-(3,7-dimethyloctyl)-5,7,8-trimethyl-4-oxochroman-2-ylmethoxy]phenyl}-2-chloropropionate(Step D3)

Following the same procedure as described in Preparation 18, 1.6 g of6-acetoxy-2-(4-aminophenoxymethyl)-2-(3,7-dimethyloctyl)-5,7,8-trimethylchroman-4-one(prepared as described in Preparation 32), 0.28 g of sodium nitrite, 1.7ml of concentrated hydrochloric acid, 3.3 ml of ethyl acrylate and 0.1 gof cuprous oxide were reacted, to give the title compound.

Rf value on silica gel thin layer chromatography=0.45 (developingsolvent, benzene:ethyl acetate=20:1 by volume).

Nuclear Magnetic Resonance Spectrum (CDCl₃) δ ppm: 0.86 (9H, doublet,J=7 Hz); 1.0-2.0 (12H, multiplet); 1.24 (3H, triplet, J=7 Hz); 2.09 (3H,singlet); 2.13 (3H, singlet); 2.33 (3H, singlet); 2.42 (3H, singlet);2.80 & 2.98 (2H, AB type, J=16 Hz); 3.07 (1H, doublet of doublets, J=7 &14 Hz); 3.31 (1H, doublet of doublets, J=7 & 14 Hz); 4.06 (2H, singlet);4.18 (2H, quartet, J=7 Hz); 4.37 (1H, triplet, J=7 Hz); 6.83 (2H,doublet, J=9 Hz); 7.15 (2H, doublet, J=9 Hz).

PREPARATION 346-Methoxymethoxy-2,5,7,8-tetramethyl-2-(5-nitropyridin-2-yloxymethyl)chroman(Step A2, Introduction of Aromatic group)

0.96 g of a 55% w/w suspension of sodium hydride in mineral oil waswashed 4 times with cyclohexane and then slowly added to a mixture of5.0 g of 2-hydroxymethyl-6-methoxymethoxy-2,5,7,8-tetramethylchroman(prepared as described in Preparation 1 of copending U.S. Ser. No.644,996) and 20 ml of dimethylformamide, under a nitrogen stream at roomtemperature. The reaction mixture was heated at 50° C. for 10 minutesand then cooled to 10° C. 4.2 g of 2-chloro-5-nitropyridine were thenadded in limited amounts. The reaction mixture was allowed to standovernight at room temperature and poured into water. The resultingmixture was extracted with benzene. The extract was washed with waterand dried over sodium sulfate. The solvent was distilled off underreduced pressure, and the residue was purified by silica gel columnchromatography, eluted with a 25:1 by volume mixture of benzene andethyl acetate, to give the title compound.

Rf value on silica gel thin layer chromatography=0.56 (developingsolvent, benzene:ethyl acetate=10:1 by volume).

Nuclear Magnetic Resonance Spectrum (CDCl₃) δ ppm: 1.40 (3H, singlet);1.7-2.3 (2H, multiplet); 2.02 (3H, singlet); 2.17 (6H, singlet); 2.65(2H, broad triplet, J=6 Hz); 3.61 (3H, singlet); 4.51 (2H, singlet);4.88 (2H, singlet); 6.87 (1H, doublet, J=9 Hz); 8.37 (1H, doublet ofdoublets, J=9 & 3 Hz); 9.06 (1H, doublet, J=3 Hz).

PREPARATION 356-Hydroxy-2,5,7,8-tetramethyl-2-(5-nitropyridin-2-yloxymethyl)chroman(Step A3, Deprotection)

1 g of 10% w/v aqueous sulfuric acid was added to 45 ml of acetic acidcontaining 5.2 g of6-methoxymethoxy-2,5,7,8-tetramethyl-2-(5-nitropyridin-2-yloxymethyl)chromanprepared as described in Preparation 34), and the resulting mixture washeated at 55°-58° C. for 15 minutes. The reaction mixture was cooled,poured into a mixture of 75 g of sodium bicarbonate and 75 g of ice, andthen extracted with ethyl acetate. The extract was washed with water anddried over anhydrous sodium sulfate. The solvent was distilled off underreduced pressure. The residue gave the title compound as a light-brownoil.

Rf value on silica gel thin layer chromatography=0.46 developingsolvent, benzene:ethyl acetate=10:1 by volume).

Nuclear Magnetic Resonance Spectrum (CDCl₃) δ ppm: 1.39 (3H, singlet);1.7-2.3 (2H, multiplet); 2.05 (3H, singlet); 2.11 (3H, singlet); 2.15(3H, singlet); 2.67 (2H, broad triplet, J=6 Hz); 4.19 (1H, singlet,disappeared on adding heavy water); 4.50 (2H, singlet), 6.85 (1H,doublet, J=9 Hz); 8.36 (1H, doublet of doublets, J=9 & 3 Hz); 9.06 (1H,doublet, J=3 Hz).

PREPARATION 366-Acetoxy-2,5,7,8-tetramethyl-2-(5-nitropyridin-2-yloxymethyl)chroman(Step A3, Acylation)

Following the same procedure as described in Preparation 16, 5.2 g of6-hydroxy-2,5,7,8-tetramethyl-2-(5-nitropyridin-2-yloxymethyl)chroman(prepared as described in Preparation 35), 3 ml of acetic anhydride, 3ml of pyridine and about 20 ml of benzene were reacted to give the titlecompound.

Rf value on silica gel thin layer chromatography=0.52 (developingsolvent, benzene:ethyl acetate=10:1 by volume).

Nuclear Magnetic Resonance Spectrum (CDCl₃) δ ppm: 1.40 (3H, singlet);1.7-2.3 (2H , multiplet); 2.02 (9H, singlet); 2.32 (3H, singlet); 2.69(2H, broad triplet, J=6 Hz); 4.52 (2H, AB type, J=12 Hz); 6.86 (1H,doublet, J=9 Hz); 8.36 (1H, doublet of doublets, J=9 & 3 Hz); 9.07 (1H,doublet, J=3 Hz).

PREPARATION 376-Acetoxy-2-(5-aminopyridin-2-yloxymethyl)-2,5,7,8-tetramethylchroman(Step A3, Hydrogenation)

6 g of6-acetoxy-2,5,7,8-tetramethyl-2-(5-nitropyridin-2-yloxymethyl)chroman(prepared as described in Preparation 36) were dissolved in a mixture of80 ml of methanol and 15 ml of benzene, and, in the presence of 1.5 g of10% w/w palladium-on-carbon, were catalytically reduced at roomtemperature for about 20 hours under about 1 atmosphere (about 1 bar)pressure of hydrogen. The catalyst was filtered off, and the filtratewas condensed by evaporation under reduced pressure, to give the titlecompound.

Rf value on silica gel thin layer chromatography=0.04 (developingsolvent, benzene:ethyl acetate=10:1 by volume).

Nuclear Magnetic Resonance Spectrum (CDCl₃) δ ppm: 1.39 (3H, singlet);1.6-2.4 (2H, multiplet); 1.97 (3H, singlet); 2.01 (3H, singlet); 2.07(3H, singlet); 2.30 (3H, singlet); 2.64 (2H, broad triplet, J=6 Hz); 3.9(2H, broad singlet, disappeared on adding heavy water); 4.25 (2H, ABtype, J=12 Hz); 6.61 (1H, doublet, J=9 Hz); 7.02 (1H, doublet ofdoublets, J=9 & 3 Hz); 7.64 (1H, doublet, J=3 Hz).

PREPARATION 38 Ethyl3-[2-(6-acetoxy-2,5,7,8-tetramethylchroman-2-yl-methoxy)pyridin-5-yl]-2-chloropropionate(Step A4)

Following the same procedure as described in Preparation 18, 4.5 g of6-acetoxy-2-(5-aminopyridin-2-yloxymethyl)-2,5,7,8-tetramethylchroman(prepared as described in Preparation 37), 1.1 g of sodium nitrite, 5 mlof concentrated hydrochloric acid, 10 g of ethyl acrylate, 175 mg ofcuprous oxide, 40 ml of acetone and about 2.5 g of water were reacted,to give the title compound.

Rf value on silica gel thin layer chromatography=0.45 (developingsolvent, benzene:ethyl acetate=10:1 by volume).

Nuclear Magnetic Resonance Spectrum (CDCl₃) δ ppm: 1.26 (3H, triplet,J=7.5 Hz); 1.40 (3H, singlet); 1.7-2.3 (2H, multiplet); 1.99 (3H,singlet); 2.02 (3H, singlet); 2.07 (3H, singlet); 2.31 (3H, singlet);2.65 (2H, broad triplet, J=6 Hz); 3.07 (1H, doublet of doublets, J=13.5& 7.5 Hz); 3.30 (1H, doublet of doublets, J=13.5 & 7.5 Hz); 4.0-4.5 (5H,multiplet); 6.72 (1H, doublet, J=9 Hz); 7.48 (1H, doublet of doublets,J=9 & 3 Hz); 8.02 (1H, doublet, J=3 Hz).

PREPARATION 39 5-Acetoxy-4-t-butyl-2-hydroxyacetophenone

A mixture of 100 g of t-butylhydroquinone, 130 ml of acetic anhydrideand 1 kg of a boron trifluoride-acetic acid complex salt (borontrifluoride content 40%) was heated for 2 hours at 60° C. whilststirring, and was then heated for a further 2 hours at 90° C. Thereaction mixture was cooled, and then it was poured into 3 liters ofice-water and extracted with benzene. The benzene extract was washedwith a saturated aqueous solution of sodium bicarbonate and then withwater and dried over anhydrous sodium sulfate. The solvent was distilledoff and the resulting oily residue was purified by silica gel columnchromatography eluted with benzene, to give the title compound, meltingat 86.5°-87.5° C.

PREPARATION 406-Acetoxy-7-t-butyl-2-methyl-2-(2-methyl-5-nitrophenoxymethyl)chroman-4-one(Step D1)

Following the same procedure as described in Preparation 19, 4.78 g of5-acetoxy-4-t-butyl-2-hydroxyacetophenone (prepared as described inPreparation 39), 4.0 g of 1-(2-methyl-5-nitrophenoxy)propan-2-one, 2.0 gof pyrrolidine, 50 ml of benzene, 4 ml of acetic anhydride and 50 ml ofpyridine were reacted, to give the title compound, as a slightly red,foamy substance.

Rf value on silica gel thin layer chromatography=0.24 (developingsolvent, benzene:ethyl acetate=20:1 by volume).

Nuclear Magnetic Resonance Spectrum [(CD₃)₂ CO] δ ppm: 1.32 (9H,singlet); 1.63 (3H, singlet); 2.17 (3H, singlet); 2.32 (3H, singlet);2.90 (1H, doublet, J=16.5 Hz); 3.15 (1H, doublet, J=16.5 Hz); 4.43 (2H,AB type, J=12 Hz); 6.97 (1H, singlet); 7.38 (1H, doublet, J=8 Hz); 7.45(1H, singlet); 7.70-7.90 (2H, multiplet).

PREPARATION 416-Acetoxy-2-(5-amino-2-methylphenoxymethyl)-7-t-butyl-2-methylchroman-4-one(Step D2)

Following the same procedure as described in Preparation 24,hydrogenation of 7.3 g of6-acetoxy-7-t-butyl-2-methyl-2-(2-methyl-5-nitrophenoxymethyl)chroman-4-one(prepared as described in Preparation 40) in the presence of 1 g of 10%w/w palladium-on-carbon and 100 ml of ethanol gave the title compound asa slightly red, foamy substance.

Rf value on silica gel thin layer chromatography=0.13 (developingsolvent, benzene:ethyl acetate=5:1 by volume).

Nuclear Magnetic Resonance Spectrum [(CD₃)₂ CO] δ ppm: 1.33 (9H,singlet); 1.56 (3H, singlet); 1.95 (3H, singlet); 2.31 (3H, singlet);2.80 (1H, doublet, J=16.5 Hz); 3.10 (1H, doublet, J=16.5 Hz); 4.06 (2H,singlet); 3.90-4.70 (2H, broad, disappeared on adding heavy water); 6.18(1H, doublet of doublets, J=8 & 1.5 Hz); 6.28 (1H, doublet, J=1.5 Hz);6.78 (1H, doublet, J=8 Hz); 7.00 (1H, singlet); 7.47 (1H, singlet).

PREPARATION 42 Ethyl3-[3-(6-acetoxy-7-t-butyl-2-methyl-4-oxochroman-2-ylmethoxy)-4-methylphenyl]-2-chloropropionate(Step D3)

Following the same procedure as described in Preparation 25, 5.53 g of6-acetoxy-2-(5-amino-2-methylphenoxymethyl)-7-t-butyl-2-methylchroman-4-one(prepared as described in Preparation 41), 1.2 g of sodium nitrite, 2.4ml of concentrated hydrochloric acid, 14 ml of ethyl acrylate, 190 ml ofcuprous oxide and 50 ml of acetone were reacted, to give the titlecompound as a pale yellow oil.

Rf value on silica gel thin layer chromatography=0.41 (developingsolvent, benzene:ethyl acetate=10:1 by volume).

Nuclear Magnetic Resonance Spectrum (CDCl₃) δ ppm: 1.22 (3H, triplet,J=7.5 Hz); 1.32 (9H, singlet); 1.57 (3H, singlet); 2.10 (3H, singlet);2.30 (3H, singlet); 2.74 (1H, doublet, J=17 Hz); 2.94-3.25 (1H, nd);3.08 (1H, doublet, J=17 Hz); 3.33 (1H, doublet of doublets, J=7 & 14Hz); 3.99 & 4.11 (2H, AB type, J=10 Hz); 4.18 (2H, quartet, J=7.5 Hz);4.40 (1H, triplet, J=7 Hz); 6.65-6.85 (2H, nd); 6.99 (1H, singlet); 7.07(1H, doublet, J=7.5 Hz); 7.50 (1H, singlet).

PREPARATION 436-Acetoxy-2-hydroxy-5,7,8-trimethyl-2-(4-nitrophenoxymethyl)chroman-4-one(Step H1)

A solution of 3 g of potassium t-butoxide in 100 ml of tetrahydrofuranwas added dropwise to a solution of 15 g of3-acetoxy-2,4,5-trimethyl-6-(4-nitrophenoxyacetoxy)acetophenone in 1liter of tetrahydrofuran, whilst ice-cooling, and the resulting mixturewas stirred at the same temperature for 2.5 hours. The reaction mixturewas then poured into a mixture of ethyl acetate and an aqueous solutionof sodium chloride, and the organic layer was separated and dried overanhydrous sodium sulfate. The solvent was distilled off. The residue waspurified by silica gel column chromatography, eluted with a 1:1 byvolume mixture of hexane and ethyl acetate, to give the title compound,melting at 204°-207° C.

Nuclear Magnetic Resonance Spectrum [(CD₃)₂ SO] δ ppm: 2.05 (3H,singlet); 2.11 (3H, singlet); 2.34 (6H, singlet); 2.76 (1H, doublet,J=17 Hz); 3.24 (1H, doublet, J=17 Hz); 4.28 & 4.50 (2H, AB type, J=10Hz); 7.24 (2H, doublet, J=9 Hz); 7.30 (1H, singlet, disappeared onadding heavy water); 8.24 (2H, J=9 Hz).

PREPARATION 446-Acetoxy-2-(4-aminophenoxymethyl)-2-hydroxy-5,7,8-trimethylchroman-4-one(Step H2)

Following the same procedure as described in Preparation 24, 7 g of6-acetoxy-2-hydroxy-5,7,8-trimethyl-2-(4-nitrophenoxymethyl)chroman-4-one(prepared as described in Preparation 43) were treated with 5 g of 10%w/w palladium-on-carbon, 100 ml of tetrahydrofuran and 100 ml ofethanol, to give the title compound.

Rf value on silica gel thin layer chromatography=0.48 (developingsolvent, ethyl acetate).

Nuclear Magnetic Resonance Spectrum (CDCl₃) δ ppm: 2.08 (3H, singlet);2.10 (3H, singlet); 2.32 (3H, singlet); 2.41 (3H, singlet); 2.78 & 3.03(2H, AB type, J=16 Hz); 3.4-4.3 (3H, broad singlet, disappeared onadding heavy water); 3.98 & 4.12 (2H, AB type, J=10 Hz); 6.62 (2H,doublet, J=9 Hz); 6.80 (2H, doublet, J=9 Hz).

PREPARATION 45 Ethyl3-[4-(6-acetoxy-2-hydroxy-5,7,8-trimethyl-4-oxochroman-2-ylmethoxy)phenyl]-2-chloropropionate(Step H3)

Following the same procedure as described in Preparation 18, 3.4 g of6-acetoxy-2-(4-aminophenoxymethyl)-2-hydroxy-5,7,8-trimethylchroman-4-one(prepared as described in Preparation 44), 40 ml of acetone, 5 ml of 35%w/v aqueous hydrochloric acid, 1.2 g of sodium nitrite, 1.6 ml of water,13 g of ethyl acrylate and 0.32 g of cuprous oxide were reacted, to givethe title compound.

Rf value on silica gel thin layer chromatography=0.20 (developingsolvent, hexane:ethyl acetate=2:1 by volume).

Nuclear Magnetic Resonance Spectrum (CDCl₃) δ ppm: 1.24 (3H, triplet,J=7 Hz); 2.09 (6H, singlet); 2.33 (3H, singlet); 2.42 (3H, singlet);2.5-3.6 (4H, nd); 3.9-4.6 (5H, nd); 6.93 (2H, doublet, J=9 Hz); 7.20(2H, doublet, J=9 Hz).

PREPARATION 46 Ethyl3-[4-(6-acetoxy-2,5,7,8-tetramethylchroman-2-yl-methoxy)phenyl]-2-chloro-2-methylpropionate(Step A4)

Following the same procedure as described in Preparation 18, 2 g of6-acetoxy-2-(4-aminophenoxymethyl)-2,5,7,8-tetramethylchroman (preparedas described in Preparation 50), 25 ml of acetone, 3 ml of 35% w/vaqueous hydrochloric acid, 0.7 g of sodium nitrite, 1 ml of water, 8 gof ethyl methacrylate and 0.2 g of cuprous oxide were reacted, to givethe title compound.

Rf value on silica gel thin layer chromatography=0.54 (developingsolvent, hexane:ethyl acetate=2:1 by volume).

Nuclear Magnetic Resonance Spectrum (CDCl₃) δ ppm: 1.29 (3H, triplet,J=7 Hz); 1.43 (3H, singlet); 1.68 (3H, singlet); 1.98 (3H, singlet);2.03 (3H, singlet); 2.09 (3H, singlet); 2.32 (3H, singlet); 1.5-2.5 (2H,nd); 2.62 (2H, broad triplet, J=7 Hz); 3.18 & 3.36 (2H, AB type, J=17Hz); 3.84 & 3.98 (2H, AB type, J=9 Hz); 4.21 (2H, quartet, J=7 Hz); 6.84(2H, doublet, J=9 Hz); 7.14 (2H, doublet, J=9 Hz).

PREPARATION 476-Acetoxy-2,5,7,8-tetramethyl-2-(4-nitrophenoxymethyl)chroman-4-one(Step D1)

(a) A mixture of 17.7 g of5-acetoxy-2-hydroxy-3,4,6-trimethylacetophenone, 14.6 g of4-nitrophenoxyacetone, 7.5 g of pyrrolidine and 60 ml of benzene wasallowed to stand for 1 day at room temperature, and then heated underreflux for 7 hours using a water separator. Water and ethyl acetate wereadded to the reaction mixture. The organic layer was separated and driedover anhydrous sodium sulfate. The solvent was distilled off and theresulting residue was purified by silica gel column chromatography usinga 2:1 by volume mixture of hexane and ethyl acetate as eluent, to givethe title compound.

Rf value on silica gel thin layer chromatography=0.17 (developingsolvent, hexane:ethyl acetate=3:1 by volume).

Nuclear Magnetic Resonance Spectrum (CDCl₃) δ ppm: 1.56 (3H, singlet);2.10 (6H, singlet); 2.36 (3H, singlet); 2.43 (3H, singlet); 2.70 (1H,doublet, J=15 Hz); 3.06 (1H, doublet, J=15 Hz); 4.11 (1H, doublet, J=10Hz); 4.24 (1H, doublet, J=10 Hz); 6.98 (2H, doublet, J=9 Hz); 8.20 (2H,doublet, J=9 Hz).

(b) A mixture of the same components as mentioned in (a), but containingpiperidine instead of pyrrolidine, was heated under reflux for 3 hoursusing a water separator. 5% w/v aqueous hydrochloric acid was added, andthe reaction mixture was extracted with benzene. The benzene extract waswashed with water and dried over anhydrous sodium sulfate. The solventwas distilled off to give the title compound. The Rf value and nuclearmagnetic resonance spectrum of this compound accorded with those of thecompound obtained in (a).

(c) In a similar manner to (b), the use of morpholine instead ofpiperidine afforded the title compound. The Rf value and nuclearmagnetic resonance spectrum of this compound accorded with those of thecompound obtained in (a).

(d) A mixture of the same components as mentioned in (a), but containingmorpholine instead of pyrrolidine, and toluene instead of benzene, washeated under reflux for 1 hour. Then, in a similar manner to (b), thetitle compound was obtained. The Rf value and nuclear magnetic resonancespectrum of this compound accorded with those of the compound obtainedin (a).

PREPARATION 486-Acetoxy-4-hydroxy-2,5,7,8-tetramethyl-2-(4-nitrophenoxymethyl)chroman(Step F1)

160 mg of sodium borohydride were added to a mixture of 1.8 g of6-acetoxy-2,5,7,8-tetramethyl-2-(4-nitrophenoxymethyl)chroman-4-one(prepared as described in Preparation 47), 15 ml of methanol and 1 ml ofbenzene in an ice bath, and the mixture was stirred for 30 minutes. Thereaction mixture was then poured into ice-water, neutralized with 10%w/v aqueous hydrochloric acid and extracted with benzene. The benzeneextract was washed with water and dried over anhydrous sodium sulfate.The solvent was distilled off under reduced pressure. The residue waspurified by silica gel column chromatography eluted with a 9:1 by volumemixture of benzene and ethyl acetate, to give crystals. These crystalswere recrystallized from a mixture of benzene and hexane to give thetitle compound, melting at 139°-141° C.

Nuclear Magnetic Resonance Spectrum (CDCl₃) δ ppm: 1.56 (3H, singlet);2.05 (6H, singlet); 2.0-2.4 (2H, nd); 2.19 (3H, singlet); 2.33 (3H,singlet); 4.10 (2H, AB type, J=9 Hz); 5.0 (1H, doublet of doublets, J=3& 9 Hz); 7.03 (2H, doublet, J=9 Hz); 8.23 (2H, doublet, J=9 Hz).

PREPARATION 496-Acetoxy-2,5,7,8-tetramethyl-2-(4-nitrophenoxymethyl)-2H-chromene (StepF3)

Following the procedure described in Preparation 57, 160 mg of6-acetoxy-4-hydroxy-2,5,7,8-tetramethyl-2-(4-nitrophenoxymethyl)chroman(prepared as described in Preparation 48), 10 mg of p-toluenesulfonicacid and 2 ml of benzene gave the title compound.

Rf value on silica gel thin layer chromatography=0.49 (developingsolvent, benzene:ethyl acetate=20:1 by volume).

Nuclear Magnetic Resonance Spectrum (CDCl₃) δ ppm: 1.59 (3H, singlet);2.03 (3H, singlet); 2.05 (3H, singlet); 2.09 (3H, singlet); 2.33 (3H,singlet); 4.10 (2H, AB type, J=9 Hz); 5.73 (1H, doublet, J=10 Hz); 6.73(1H, doublet, J=10 Hz); 6.96 (2H, doublet, J=9 Hz); 8.22 (2H, doublet,J=9 Hz).

PREPARATION 506-Acetoxy-2-(4-aminophenoxymethyl)-2,5,7,8-tetramethylchroman (Step F5)

Following the procedure described in Preparation 58, 100 mg of6-acetoxy-2,5,7,8-tetramethyl-2-(4-nitrophenoxymethyl)-2H-chromene(prepared as described in Preparation 49) were dissolved in 2 ml ofmethanol and, in the presence of 20 mg of 10% w/w palladium-on-carbon,the compound was reduced under 1 atmosphere (about 1 bar) pressure ofhydrogen, to give the title compound melting at 138°-140° C.

Nuclear Magnetic Resonance Spectrum (CDCl₃) δ ppm: 1.42 (3H, singlet);2.00 (3H, singlet); about 2 (2H, multiplet); 2.04 (3H, singlet); 2.10(3H, singlet); 2.31 (3H, singlet); 2.6 (2H, broad triplet, J=6 Hz); 3.37(2H, broad, disappeared on adding heavy water); 3.80 & 3.95 (2H, ABtype, J=9 Hz); 6.62 (2H, doublet, J=7.5 Hz); 6.78 (2H, doublet, J=7.5Hz).

PREPARATION 51 Ethyl3-[4-(6-acetoxy-2,5,7,8-tetramethylchroman-2-ylmethoxy)phenyl]-2-chloropropionate(Step A4)

17.5 g of 6-acetoxy-2-(4-aminophenoxymethyl)-2,5,7,8-tetramethylchroman(prepared as described in Preparation 50) were dissolved in a mixture of130 ml of acetone and 30 ml of water. 13 ml of concentrated hydrochloricacid, and then 8.5 ml of water containing 4.3 g of sodium nitrite, wasadded dropwise to this solution in an ice bath. A further 37.3 ml ofethyl acrylate were then added dropwise, and then the reaction mixturewas heated to 40°-43° C.; at this temperature, 680 mg of cuprous oxidewere added slowly. After about 30 minutes, nitrogen generation finished.The reaction mixture, which had separated into two layers, was mixedwith benzene to extract the organic layer. The benzene extract waswashed with a saturated aqueous solution of sodium chloride and thendried over anhydrous sodium sulfate. The solvent was distilled off andthe resulting dark brown oil was subjected to silica gel columnchromatography. After the first elution with a 1:1 by volume mixture ofbenzene and cyclohexane, the title compound was obtained from the nextelution with a 2:1 by volume mixture of benzene and cyclohexane and fromthe subsequent elution with benzene alone.

Rf value on silica gel thin layer chromatography=0.39 (developingsolvent, benzene:ethyl acetate=20:1 by volume).

Nuclear Magnetic Resonance Spectrum (CDCl₃) δ ppm: 1.23 (3H, triplet,J=7.5 Hz); 1.42 (3H, singlet); about 2 (2H, multiplet); 1.98 (3H,singlet); 2.04 (3H, singlet); 2.09 (3H, singlet); 2.31 (3H, singlet);2.6 (2H, broad triplet, J=6 Hz); 3.05 (1H, doublet of doublets, J=15 &7.5 Hz); 3.31 (1H, doublet of doublets, J=15 & 7.5 Hz); 3.83 & 3.99 (2H,AB type, J=9 Hz); 4.18 (2H, quartet, J=7.5 Hz); 4.38 (1H, triplet, J=7.5Hz); 6.85 (2H, doublet, J=9 Hz); 7.14 (2H, doublet, J=9 Hz).

PREPARATION 526-Hydroxy-2,5,7,8-tetramethyl-2-(4-nitrophenoxymethyl)chroman-4-one(Step D1)

A mixture of 3.9 g of 2,5 -dihydroxy-3,4,6-trimethylacetophenone, 3.9 gof 4-nitrophenoxyacetone, 2.0 g of pyrrolidine and 15 g of toluene wasallowed to stand for 2 days at room temperature. Dilute hydrochloricacid was then added to the reaction mixture and the mixture wasextracted with diethyl ether. The aqueous layer was further extractedwith ethyl acetate. The ethyl acetate extract and the ethereal extractwere combined and dried over anhydrous sodium sulfate. The solvent wasdistilled off and hexane was added to the resulting residue. Thecrystals which separated were collected by filtration and purified bysilica gel column chromatography using a 5:1 by volume mixture of hexaneand ethyl acetate as eluent. Recrystallization of the product from ethylacetate gave the title compound, melting at 199°-204° C.

Nuclear Magnetic Resonance Spectrum [(CD₃)₂ SO] δ ppm: 1.43 (3H,singlet); 2.01 (3H, singlet); 2.14 (3H, singlet); 2.46 (3H, singlet);2.67 (1H, doublet, J=16 Hz); 3.03 (1H, doublet, J=16 Hz); 4.31 (2H,singlet); 7.19 (2H, doublet, J=9 Hz); 7.92 (1H, singlet); 8.21 (2H,doublet, J=9 Hz).

PREPARATION 537-t-Butyl-6-hydroxy-2-methyl-2-(4-nitrophenoxymethyl)chroman-4-one (StepD1)

Following the procedure described in Preparation 52, the title compoundwas prepared from 2.0 g of 4-t-butyl-2,5-dihydroxyacetophenone, 1.9 g of4-nitrophenoxyacetone, 1.0 g of pyrrolidine and 10 ml of benzene. Thecompound obtained melted at 205°-209° C.

Nuclear Magnetic Resonance Spectrum [(CD₃)₂ CO] δ ppm: 1.39 (3H,singlet); 1.53 (9H, singlet); 2.70 (1H, doublet, J=16.5 Hz); 3.05 (1H,doublet, J=16.5 Hz); 4.37 (2H, singlet); 6.80 (1H, singlet); 7.18 (2H,doublet, J=10 Hz); 7.22 (1H, singlet); 8.22 (2H, doublet, J=10 Hz); 8.31(1H, singlet, disappeared on adding heavy water).

PREPARATION 54

6-Acetoxy-7-t-butyl-2-methyl-2-(4-nitrophenoxymethyl)chroman-4-one

A mixture of 1.7 g of7-t-butyl-6-hydroxy-2-methyl-2-(4-nitrophenoxymethyl)chroman-4-one(prepared as described in Preparation 53), 1 ml of acetic anhydride and10 ml of pyridine was allowed to stand for 1 day at room temperature.The reaction mixture was then poured into ice-water, stirred for 2 hoursand extracted with benzene. The benzene extract was washed with 3Naqueous hydrochloric acid, water, a saturated aqueous solution of sodiumbicarbonate and water in that order, and then dried over anhydroussodium sulfate. The solvent was distilled off under reduced pressure andthe resulting residue was recrystallized from a mixture of benzene andethyl acetate (about 10:1 by volume) to give the title compound, meltingat 82°-84° C.

Nuclear Magnetic Resonance Spectrum [(CD₃)₂ CO] δ ppm: 1.33 (9H,singlet); 1.57 (3H, singlet); 2.33 (3H, singlet); 2.82 (1H, doublet,J=16.5 Hz); 3.13 (1H, doublet, J=16.5 Hz); 4.42 (2H, singlet); 6.93 (1H,singlet); 7.25 (2H, doublet, J=9 Hz); 7.44 (1H, singlet); 8.22 (2H,doublet, J=9 Hz).

PREPARATION 557-t-Butyl-4,6-dihydroxy-2-methyl-2-(4-nitrophenoxymethyl)chroman (StepF1)

A solution of 3.0 g of6-acetoxy-7-t-butyl-2-methyl-2-(4-nitrophenoxymethyl)chroman-4-one(prepared as described in Preparation 54) in 20 ml of tetrahydrofuranwas dropped into a suspension containing 0.3 g of sodium borohydride in10 ml of methanol whilst stirring over an ice bath. After the whole ofthe solution had been added, the reaction mixture was stirred for 2hours at room temperature. The reaction mixture was then ice-cooledagain, acidified weakly with 10% w/v aqueous hydrochloric acid andextracted with ethyl acetate. The ethyl acetate extract was washed withwater and dried over anhydrous sodium sulfate. The solvent was removedby evaporation under reduced pressure to give crystals.Recrystallization of these crystals from a mixture of benzene andpetroleum ether gave the title compound, melting at 194°-201° C.

Nuclear Magnetic Resonance Spectrum [(CD₃)₂ CO] δ ppm: 1.34 (9H,singlet); 1.50 (3H, singlet); 1.88 (1H, doublet of doublets, J=13.5 & 9Hz); 2.45 (1H, doublet of doublets, J=13.5 & 6 Hz); 2.78 (1H, singlet,disappeared on adding heavy water); 4.15 (2H, singlet); 4.75 (1H,multiplet); 6.62 (1H, singlet); 6.91 (1H, singlet); 7.15 (2H, doublet,J=9 Hz); 8.20 (2H, doublet, J=9 Hz).

PREPARATION 564,6-Diacetoxy-7-t-butyl-2-methyl-2-(4-nitrophenoxymethyl)chroman (StepF2)

3 ml of acetic anhydride were added to a mixture of 2.0 g of7-t-butyl-4,6-dihydroxy-2-methyl-2-(4-nitrophenoxymethyl)chroman(prepared as described in Preparation 55) and 20 ml of pyridine, and themixture was heated for 3 hours at 50° C. The reaction mixture was thendissolved in benzene and washed with 3N aqueous hydrochloric acid,water, a saturated aqueous solution of sodium bicarbonate and water inthat order, and then dried over anhydrous sodium sulfate. The solventwas distilled off to give the title compound as a slightly yellow oil.

Rf value on silica gel thin layer chromatography=0.62 (developingsolvent, benzene:ethyl acetate=5:1 by volume).

Nuclear Magnetic Resonance Spectrum [(CD₃)₂ CO] δ ppm: 1.31 (9H,singlet); 1.55 (3H, singlet); 1.77 (3H, singlet); 2.0-2.3 (1H, nd); 2.27(3H, singlet); 2.45-2.7 (1H, nd); 4.20 & 4.38 (2H, AB type, J=10 Hz);5.85-6.10 (1H, multiplet); 6.87 (1H, singlet); 6.98 (1H, singlet); 7.20(2H, doublet, J=9 Hz); 8.30 (2H, doublet, J=9 Hz).

PREPARATION 576-Acetoxy-7-t-butyl-2-methyl-2-(4-nitrophenoxymethyl)-2H-chromene (StepF4)

A mixture of 2.4 g of4,6-diacetoxy-7-t-butyl-2-methyl-2-(4-nitrophenoxymethyl)chroman(prepared as described in Preparation 56), 0.1 g of p-toluenesulfonicacid monohydrate and 50 ml of benzene was heated under reflux for 1hour. The reaction solution was cooled, washed with a saturated aqueoussolution of sodium bicarbonate, and then with water, and dried overanhydrous sodium sulfate. The solvent was distilled off under reducedpressure, to give the title compound as a yellow oil.

Rf value on silica gel thin layer chromatography=0.58 (developingsolvent, benzene:ethyl acetate=10:1 by volume).

Nuclear Magnetic Resonance Spectrum [(CD₃)₂ CO] δ ppm: 1.27 (9H,singlet); 1.54 (3H, singlet); 2.27 (3H, singlet); 4.28 (2H, singlet);5.79 (1H, doublet, J=10 Hz); 6.52 (1H, doublet, J=10 Hz); 6.67 (1H,singlet); 6.76 (1H, singlet); 7.13 (2H, doublet, J=9 Hz); 8.20 (2H,doublet, J=9 Hz).

PREPARATION 586-Acetoxy-2-(4-aminophenoxymethyl)-7-t-butyl-2-methylchroman (Step F5)

2.1 g of6-acetoxy-7-t-butyl-2-methyl-2-(4-nitrophenoxymethyl)-2H-chromene(prepared as described in Preparation 57) were dissolved in a mixture of20 ml of benzene and 2 ml of acetic acid, and the compound was reducedfor 10 hours at room temperature, in the presence of 0.1 g of 10% w/wpalladium-on-carbon, and under about 1 atmosphere (about 1 bar) pressureof hydrogen. The catalyst was filtered off, and the reaction mixture waswashed with a saturated aqueous solution of sodium bicarbonate and thenwith water, after which it was dried over anhydrous sodium sulfate. Thesolvent was distilled off under reduced pressure, and the resultingresidue was purified by silica gel column chromatography, eluted withbenzene, to give the title compound as a slightly brown oil.

Rf value on silica gel thin layer chromatography=0.13 (developingsolvent, benzene:ethyl acetate=10:1 by volume).

Nuclear Magnetic Resonance Spectrum [(CD₃)₂ CO] δ ppm: 1.30 (9H,singlet); 1.40 (3H, singlet); 1.7-2.2 (2H, nd); 2.27 (3H, singlet); 2.73(2H, broad triplet, J=7 Hz); 3.89 (2H, singlet); 3.7-4.5 (2H, broad,disappeared on adding heavy water); 6.50-7.05 (6H, multiplet).

PREPARATION 59 Ethyl3-[4-(6-acetoxy-7-t-butyl-2-methylchroman-2-ylmethoxy)phenyl)-2-chloropropionate(Step A4)

Following the procedure described in Preparation 51, 1.74 g of6-acetoxy-2-(4-aminophenoxymethyl)-7-t-butyl-2-methylchroman (preparedas described in Preparation 58), 380 mg of sodium nitrite, 0.8 ml ofconcentrated hydrochloric acid, 4.5 g of ethyl acrylate, 65 mg ofcuprous oxide and 17 ml of acetone were reacted, to give the titlecompound as a slightly yellow oil.

Rf value on silica gel thin layer chromatography=0.55 (developingsolvent, benzene:ethyl acetate=5:1 by volume).

Nuclear Magnetic Resonance Spectrum (CDCl₃) δ ppm: 1.23 (3H, triplet,J=7.5 Hz); 1.31 (9H, singlet); 1.45 (3H, singlet); 1.63-2.20 (2H,multiplet); 2.28 (3H, singlet); 2.72 (2H, broad triplet, J=7 Hz); 3.08(1H, doublet of doublets, J=7.5 & 15 Hz); 3.30 (1H, doublet of doublets,J=7.5 & 15 Hz); 3.88 & 3.98 (2H, AB type, J=9 Hz); 4.18 (2H, quartet,J=7.5 Hz); 4.37 (1H, triplet, J=7.5 Hz); 6.73 (1H, singlet); 6.85 (1H,singlet); 6.88 (2H, doublet, J=9 Hz); 7.15 (2H, doublet, J=9 Hz).

PREPARATION 606-t-Butoxycarbonylmethoxy-2,5,7,8-tetramethyl-2-(4-nitrophenoxymethyl)chroman-4-one

A mixture of 5.6 g of sodium hydroxide, 150 ml of ethanol and 20 ml ofwater was added dropwise to a mixture of 25 g of6-acetoxy-2,5,7,8-tetramethyl-2-(4-nitrophenoxymethyl)chroman-4-one(prepared as described in Preparation 47), 30 ml of dimethylformamideand 150 ml of ethanol, whilst ice-cooling, and the reaction mixture wasstirred for 3 hours. 18.3 g of t-butyl bromoacetate were then added. Thereaction mixture was stirred for 1 hour at room temperature and thenallowed to stand overnight. After this, the reaction mixture was pouredinto water, neutralized with a 10% w/v aqueous hydrogen chloridesolution and extracted with benzene. This extract was washed with waterand dried over anhydrous sodium sulfate. The solvent was distilled offunder reduced pressure, and the residue was purified by silica gelcolumn chromatography eluted with a 20:1 by volume mixture of benzeneand ethyl acetate, to give the title compound.

Rf value on silica gel thin layer chromatography=0.49 (developingsolvent, benzene:ethyl acetate=10:1 by volume)

Nuclear Magnetic Resonance Spectrum (CDCl₃) δ ppm: 1.53 (12H, singlet);2.07 (3H, singlet); 2.27 (3H, singlet); 2.57 (3H, singlet); 2.68 (1H,doublet, J=16.5 Hz); 3.05 (1H, doublet, J=16.5 Hz); 4.17 (2H, singlet,and 2H, AB-type, J=10 Hz); 6.97 (2H, doublet, J=9 Hz); 8.19 (2H,doublet, J=9 Hz).

PREPARATION 616-Ethoxy-2,5,7,8-tetramethyl-2-(4-nitrophenoxymethyl)chroman

1.6 g of a 55% w/w suspension of sodium hydride in mineral oil was addedto a mixture of 11 g of6-hydroxy-2,5,7,8-tetramethyl-2-(4-nitrophenoxymethyl)chroman and 100 mlof dimethylformamide, and the reaction mixture was stirred for 1 hour atroom temperature. Then a mixture of 5.7 g of ethyl iodide and 5 ml ofbenzene was added dropwise, whilst ice-cooling, and the reaction mixturewas stirred for 2 hours at room temperature. The reaction mixture wasthen poured into water and extracted with benzene. This extract waswashed with water and dried over anhydrous sodium sulfate. The solventwas distilled from the extract under reduced pressure, and the residuewas purified by silica gel column chromatography eluted with a 3:7 byvolume mixture of cyclohexane and benzene, to give the title compound.

Rf value on silica gel thin layer chromatography=0.48 (developingsolvent, benzene).

Nuclear Magnetic Resonance Spectrum (CDCl₃) δ ppm: 1.39 (3H, triplet,J=7 Hz); 1.43 (3H, singlet); 1.7-2.1 (2H, nd); 2.06 (3H, singlet); 2.14(3H, singlet); 2.17 (3H, singlet); 2.63 (2H, broad triplet, J=7 Hz);3.72 (2H, quartet, J=7 Hz); 4.00 & 4.08 (2H, AB-type, J=10 Hz); 6.98(2H, doublet, J=9 Hz); 8.17 (2H, doublet, J=9 Hz).

PREPARATION 622-(4-Aminophenoxymethyl)-6-t-butoxycarboxymethoxy-2,5,7,8-tetramethylchroman-4-one

A mixture of 17 g of6-t-butoxycarbonylmethoxy-2,5,7,8-tetramethyl-2-(4-nitrophenoxymethyl)chroman-4-one(prepared as described in Preparation 60), 3.5 g of 10% w/wpalladium-on-carbon, 150 ml of methanol and 50 ml of dimethylformamidewas subjected to reduction with Paar's hydrogenation apparatus under ahydrogen pressure of 3-5 atmospheres (about 3-5 bars) for 7 hours. Thepalladium-on-carbon was then filtered off, and the solvent was distilledfrom the filtrate under reduced pressure. The residue was dissolved inbenzene, washed with water and dried over anhydrous sodium sulfate. Thissolvent was then distilled off under reduced pressure to give the titlecompound.

Rf value on silica gel thin layer chromatography=0.29 (developingsolvent, benzene:ethyl acetate=4:1 by volume).

Nuclear Magnetic Resonance Spectrum (CDCl₃) δ ppm: 1.47 (3H, singlet);1.54 (9H, singlet); 2.11 (3H, singlet); 2.26 (3H, singlet); 2.55-2.75(1H, nd); 2.57 (3H, singlet); 3.05 (1H, doublet, J=16 Hz); 3.15-3.65(2H, broad singlet); 3.90 & 4.03 (2H, AB-type, J=10 Hz); 4.17 (2H,singlet); 6.60 (2H, doublet, J=9 Hz); 6.76 (2H, doublet J=9 Hz).

PREPARATION 632-(4-Aminophenoxymethyl)-6-ethoxy-2,5,7,8-tetramethylchroman

The procedure described in Preparation 62 was repeated, except that 11 gof 6-ethoxy-2,5,7,8-tetramethyl-2-(4-nitrophenoxymethyl)chroman(prepared as described in Preparation 61), 2.2 g of 10% w/wpalladium-on-carbon, 100 ml of methanol and 30 ml of benzene were usedas the starting materials to give the title compound, melting at121°-123° C.

Nuclear Magnetic Resonance Spectrum (CDCl₃) δ ppm: 1.38 (3H, triplet,J=7 Hz); 1.40 (3H, singlet); 1.7-2.1 (2H, nd); 2.08 (3H, singlet); 2.12(3H, singlet); 2.17 (3H, singlet); 2.60 (2H, broad triplet, J=7 Hz);3.1-3.6 (2H, broad, disappeared on adding heavy water); 3.71 (2H,quartet, J=7 Hz); 3.80 & 3.91 (2H, AB-type J=10 Hz); 6.60 (2H, doublet,J=9 Hz); 6.78 (2H, doublet, J=9 Hz).

PREPARATION 64 Ethyl3-[4-(6-t-Butoxycarbonylmethoxy-2,5,7,8-tetramethyl-4-oxochroman-2-ylmethoxy)phenyl]-2-chloropropionate

16 ml of concentrated hydrochloric acid, 7 ml of an aqueous solutioncontaining 3.1 g of sodium nitrite and 37 ml of ethyl acrylate wereadded, in that order, at 5°-10° C. to a mixture of 16 g of2-(4-aminophenoxymethyl)-6-t-butoxycarbonylmethoxy-2,5,7,8-tetramethylchroman-4-one(prepared as described in Preparation 62) and 160 ml of acetone. Then0.5 g of cuprous oxide was added gradually at an internal temperature of40°-43° C. After about 30 minutes, the evolution of nitrogen had ceased.The reaction mixture was then poured into water and extracted withbenzene. This extract was washed with water and dried over anhydroussodium sulfate. The solvent was distilled from the extract under reducedpressure, and the residue was purified by silica gel columnchromatography eluted with a 9:1 by volume mixture of cyclohexane andethyl acetate, to give the title compound.

Rf value on silica gel thin layer chromatography=0.33 (developingsolvent, cyclohexane:ethyl acetate=4:1 by volume).

Nuclear Magnetic Resonance Spectrum (CDCl₃) δ ppm: 1.23 (3H, triplet,J=7,.5 Hz); 1.50 (3H, singlet); 1.53 (9H, singlet); 2.09 (3H, singlet);2.26 (3H, singlet); 2.5-2.8 (1H, nd); 2.57 (3H, singlet); 3.05 (1H,doublet, J=16 Hz); 3.07 (1H, nd); 3.32 (1H, doublet of doublets, J=7 &14 Hz); 3.98 & 4.09 (2H, AB-type, J=10 Hz); 4.05-4.35 (2H, nd); 4.18(2H, singlet); 4.37 (1H, triplet, J=7 Hz); 6.85 (2H, doublet, J=8 Hz);7.14 (2H, doublet, J=8 Hz);

PREPARATION 65 Ethyl2-chloro-3-[4-(6-ethoxy-2,5,7,8-tetramethylchroman-2-ylmethoxy)phenyl]propionate

The procedure described in Preparation 64 was repeated, except that 9.5g of 2-(4-aminophenoxymethyl)-6-ethoxy-2,5,7,8-tetramethylchroman(prepared as described in Preparation 63), 10 ml of concentratedhydrochloric acid, 2.4 g of sodium nitrite, 26.8 g of ethyl acrylate,0.4 g of cuprous oxide and 100 ml of acetone were used as the startingmaterials, to give the title compound.

Rf value on silica gel thin layer chromatography=0.30 (developingsolvent, cyclohexane:ethyl acetate=20:1 by volume).

Nuclear Magnetic Resonance Spectrum (CDCl₃) δ ppm: 1.23 (3H, triplet,J=7 Hz); 1.38 (3H, triplet, J=7 Hz); 1.41 (3H, singlet); 1.7-2.1 (2H,nd); 2.07 (3H, singlet); 2.13 (3H, singlet); 2.17 (3H, singlet); 2.60(2H, broad triplet, J=7 Hz); 3.07 (1H, doublet of doublets, J=4 & 14Hz); 3.31 (1H, doublet of doublets, J=4 & 14 Hz); 3.71 (2H, quartet, J=7Hz); 3.86 & 3.96 (2H, AB-type, J=9 Hz); 4.17 (2H, quarter, J=7 Hz); 4.36(1H, triplet, J=7.5 Hz); 6.85 (2H, doublet, J=9 Hz); 7.13 (2H, doublet,J=9 Hz).

TEST EXAMPLE 1 Toxicity

The test animals used were male mice of the ddY strain. The animals wereemployed in groups of 3. The animals of each group were administeredorally with a single test compound in a dose of 300 mg/kg body weight.The compounds employed were those prepared as described in Examples 3,4, 5 and 13. The animals were then observed for one week afteradministration, during which time they showed no abnormalities whichcould be attributed to the test compounds. All animals were alive at theend of the 1 week observation period.

In view of the substantial dose administered to each animal, the zeromortality indicates that the compounds of the invention have a very lowtoxicity.

TEST EXAMPLE 2 Effect on Hyperglycemia

The test animals employed were genetically diabetic male mice of the KKstrain, aged about 6 months. The animals were employed in groups of 3(test compounds) or 5 (control) for each test.

The test compounds were suspended in a 0.5% w/v aqueous solution ofcarboxymethylcellulose. Each test compound was administered at a dose of50 mg/kg body weight.

Within a period of about 3-24 hours after administration, blood sampleswere taken from the tip of the tail of each mouse, and the blood glucoselevel was measured in this sample by the glucose oxidase method. Theminimum glucose level (i.e. maximum decrease) was taken for each animal.

A control group was treated with similarly, except that the testcompound was omitted.

The maximum decrease in blood glucose levels was calculated for eachtest compound as a percentage of the corresponding level of the controlgroup. The results are shown in Table 29:

                  TABLE 29                                                        ______________________________________                                        Cpd. of      Blood glucose                                                    Ex. No.      level (%)                                                        ______________________________________                                        Control      100                                                              13           61.5                                                             58           67.5                                                             59           53.4                                                             ______________________________________                                    

TEST EXAMPLE 3 Effect on Aldose Reductase

Aldose reductase was separated and partially purified from bovine lensesby the method of Hayman and Kinoshita [J. Biol. Chem., 240, 877 (1965)].Enzyme activities were photometrically determined by the method of Varmaet al. [Biochem, Pharmac., 25, 2505 (1976)].

The inhibition of aldose reductase activity was determined employingeach test compound in a concentration of 1×10⁻⁵ M, and the results areas shown in Table 30.

As a control, the known compound,5-[4-(1-methylcyclohexylmethoxy)benzyl]thiazolidine-2,4-dione ("Cpd. A")was tested by the same method and the result is also shown in Table 30:

                  TABLE 30                                                        ______________________________________                                               Cpd. of                                                                              Percent                                                                Ex. No.                                                                              Inhibition                                                      ______________________________________                                               13     55.5                                                                   58     51.6                                                                   59     79.5                                                                   Cpd. A 16.2                                                            ______________________________________                                    

We claim:
 1. A compound of formula (I): ##STR619## in which: R¹represents a hydrogen atom, a C₁ -C₁₀ alkyl group or a C₇ -C₁₃ aralkylgroup;R² represents a hydrogen atom or a C₁ -C₅ alkyl group; R³represents a hydrogen atom, a C₁ -C₂₃ alkanoyl group, a C₃ -C₂₃ alkenoylgroup, a C₃ -C₂₃ alkynoyl group, a substituted C₁ -C₂₃ alkanoyl, C₃ -C₂₃alkenoyl or C₃ -C₂₃ alkynoyl group having at least one substituentselected from the group consisting of substituents (a), an aromatic acylgroup selected from the group consisting of benzoyl and naphthoyl, a 5to 8-membered heterocyclic acyl group having 1 to 3 hetero atoms of N, Sor O, a group of formula --SO₃ R⁸ where R⁶ represents a hydrogen atom,an aralkyl group where the alkyl part is C₁ -C₃ alkyl, a C₁ -C₅ alkylgroup or a C₁ -C₅ alkyl group having at least one substituent selectedfrom the group consisting of hydroxy groups and C₁ -C₅ alkoxy groups, aC₁ -C₁₀ alkyl group or a substituted C₁ -C₁₀ alkyl group having at leastone substituent selected from the group consisting of substituents (b);R⁴ represents a hydrogen atom, a C₁ -C₁₀ alkyl group or a C₁ -C₅ alkoxygroup; R⁵ represents a hydrogen atom, a C₁ -C₅ alkyl group or a C₁ -C₅alkoxy group; R⁶ and R⁷ are independently selected from the groupconsisting of hydrogen atoms, C₁ -C₁₀ alkyl groups and substituted C₁-C₁₀ alkyl groups having at least one substituent selected from thegroup consisting of substituents (b); Ar is a divalent group selectedfrom the group consisting of divalent carbocyclic aromatic groups, anddivalent heterocyclic aromatic groups formed from a pyridine, furan,thiophene or pyrrole ring; W represents a --CH₂ -- group, a >C═O group,a group of formula >CH--OR¹¹ wherein R¹¹ represents a hydrogen atom, aC₁ -C₂₃ alkanoyl group, a C₃ -C₂₃ alkenoyl group, a C₃ -C₂₃ alkynoylgroup, a substituted C₁ -C₂₃ alkanoyl, C₃ -C₂₃ alkenoyl or C₃ -C₂₃alkynoyl group having at least one substituent selected from the groupconsisting of substituents (a), an aromatic acyl group selected from thegroup consisting of benzoyl and napthoyl, a 5-8 membered heterocycliaacyl having 1 to 3 heteroatoms of N, S, or O, A C₁ -C₁₀ alkyl group or asubstituted C₁ -C₁₀ alkyl group having at least one substituent selectedfrom the group consisting of substituents (b), or a group of formula>C═N--O--R¹² in which R¹² represents a hydrogen atom, a C₁ -C₁₀ alkylgroup, a C₁ -C₁₀ alkyl group having at least one substituent selectedfrom the group consisting of substituents (b), a C₁ -C₂₃ alkanoyl group,a C₃ -C₂₃ alkenoyl group, a C₃ -C₂₃ alkynoyl group, a substituted C₁-C₂₃ alkanoyl, C₃ -C₂₃ alkenoyl or C₃ -C₂₃ alkynoyl group having atleast one substituent selected from the group consisting of substituents(a), an aromatic acyl group selected from the group consisting ofbenzoyl and naphthoyl or a heterocyclic acyl group having 1 to 3heteroatoms of N, S or O; U represents a --CH₂ -- group; or W and Utogether represent a group of formula --CH═CH--; or when W represents acarbonyl group or said group of formula >C═N--OR¹², U, R¹ and the carbonatom to which R¹ is attached together represent a group of formula--CH═C<; n is an integer of from 1 to 3; said aryl groups and the arylparts of said aralkyl, aralkyloxycarbonyl, and aromatic acyloxy being C₆-C₁₀ carbocyclic aryl groups which are unsubstituted or have at leastone substituent selected from the group consisting of substituents (c);said heterocyclic groups, heterocyclic parts of said heterocyclic acyland acyloxy groups have from 5 to 10 ring atoms, of which from 1 to 5are hetero-atoms selected from the group consisting of nitrogen, oxygenand sulfur hetero-atoms, said heterocyclic groups being unsubstituted orhaving at least one substituent selected from the group consisting ofsubstituents (d); said substituents (a) being selected from the groupconsisting of aryl groups, carboxy groups, C₂ -C₆ alkoxycarbonyl groupsand aralkyloxycarbonyl groups; said substituents (b) being selected fromthe group consisting of hydroxy groups, C₁ -C₅ alkoxy groups, arylgroups, C₁ -C₂₃ alkanoyloxy groups, C₃ -C₂₃ alkenoyloxy groups, C₃ -C₂₃alkynoyloxy groups, substituted C₁ -C₂₃ alkanoyloxy, C₃ -C₂₃ alkenoyloxyor C₃ -C₂₃ alkynoyloxy groups having at least one substituent selectedfrom the group consisting of substituents (a), aromatic acyloxy groups,heterocyclic acyloxy groups, groups of formula --COOR⁸ where R⁸ is asdefined above and groups of formula --CONR⁹ R¹⁰ whereR⁹ and R¹⁰ areindependently selected from the group consisting of hydrogen atoms andC₁ -C₅ alkyl groups or R⁹ and R¹⁰, together with the nitrogen atom towhich they are attached, represent a heterocyclic group having from 5 to7 ring atoms of which from 1 to 3 atoms, including nitrogen atom, arehetero-atoms selected from the group consisting of nitrogen, oxygen andsulfur hetero-atoms, said heterocyclic group being unsubstituted, or,where said ring atoms include an additional nitrogen hetero-atom, saidadditional nitrogen atom being unsubstituted or having a singlesubstituent selected from the group consisting of substituents (e); saidsubstituents (c) being selected from the group consisting of C₁ -C₅alkyl groups, C₁ -C₅ alkoxy groups, C₁ -C₅ alkyl groups having at leastone halogen substituent, halogen atoms, amino groups, C₁ -C₅ alkylaminogroups, dialkylamino groups in which each alkyl part is C₁ -C₅, nitrogroups, cyano groups, groups of formula --CONR₂ where R represents a C₁-C₅ alkyl group or an aryl group and hydroxy groups; and saidsubstituents (d) being selected from the group consisting of C₁ -C₅alkyl groups, C₁ -C₅ alkoxy groups and doubly bonded oxygen atoms; saidsubstituents (e) being selected from the group consisting of C₁ -C₅alkyl groups, C₁ -C₅ alkanoyl groups, C₃ -C₅ alkenoyl groups and C₃ -C₅alkynoyl groups; provided that:(α) where: R³ represents said hydrogenatom, an unsubstituted C₁ -C₆ alkanoyl group, an unsubstituted C₃ -C₆alkenoyl group, an unsubstituted C₃ -C₆ alkynoyl group, said aromaticacyl group, said heterocyclic acyl group, an aralkanoyl group or anaralkenoyl group; and R⁶ and R⁷ both represent hydrogen atoms; and Arrepresents a p-phenylene group; and W represents a group of formula>CH₂, >C═O or >CH--OR^(11x) (wherein R^(11x) represents a hydrogen atom,an unsubstituted C₁ -C₆ alkanoyl group, an unsubstituted C₃ -C₆ alkenoylgroup, an unsubstituted C₃ -C₆ alkynoyl group, said aromatic acyl group,said heterocyclic acyl group, an aralkanoyl group or an aralkenoylgroup); and U represents said group of formula >CH₂, then(i) when R¹represents a hydrogen atom or a C₁ -C₅ alkyl group, R⁴ represents a C₆-C₁₀ alkyl group, and (ii) when R⁴ represents a hydrogen atom, a C₁ -C₅alkyl group or a C₁ -C₅ alkoxy group, R¹ represents a C₆ -C₁₀ alkylgroup or said C₇ -C₁₃ aralkyl group; (β) where: R¹ and R² areindependently selected from the group consisting of hydrogen atoms andC₁ -C₅ alkyl groups; and R⁴ and R⁵ are independently selected from thegroup consisting of hydrogen atoms, C₁ -C₅ alkyl groups and C₁ -C₅alkoxy groups; and Ar represents a p-phenylene group; and W is a groupof formula >CH₂, >C═O or >CH--OR^(11x) (where R^(11x) is as definedabove); and U represents said group of formula >CH₂ ; and n is aninteger from 1 to 3, then at least one of R³, R⁶ and R⁷ represents saidalkyl or substituted alkyl group; and pharmaceutically acceptable saltsthereof.
 2. A compound as claimed in claim 1, in which:R¹ represents ahydrogen atom or a C₁ -C₁₀ alkyl group; R² represents a hydrogen atom ora C₁ -C₃ alkyl group; R³ represents a hydrogen atom, a sulfo group, a C₁-C₁₀ alkanoyl group, a C₃ -C₁₀ alkenoyl group, a substituted C₁ -C₁₀alkanoyl or C₃ -C₁₀ alkenoyl group having at least one substituentselected from the group consisting of substituents (f), an arylcarbonylgroup wherein the aryl part is a C₆ -C₁₀ carbocyclic aryl group which isunsubstituted or has at least one substituent selected from the groupconsisting of substituents (g), a group of formula R¹³ --(CH₂)_(m)--CO--, whereR¹³ represents a phenyl group or a phenyl group having atleast one substituent selected from the group consisting of substituents(g), and m is an integer from 1 to 5, a group of formula Het--CO--,whereHet represents a heterocyclic group having 5 to 6 ring atoms, ofwhich from 1 to 3 are hetero-atoms selected from the group consisting ofnitrogen oxygen and sulfur hetero-atoms, said heterocyclic group beingunsubstituted or having at least one substituent selected from the groupconsisting of C₁ -C₅ alkyl groups, a C₁ -C₅ alkyl group, a C₁ -C₅ alkylgroup substituted by a group of formula --COOR^(8a), whereR^(8a)represents a hydrogen atom, a C₁ -C₅ alkyl group or an alkoxyalkyl groupwere both the alkoxy part and the alkyl part are C₁ -C₅, a C₂ -C₅hydroxyalkyl group, a C₂ -C₅ alkyl group substituted by a group offormula --O--CO--R⁵³, whereR⁵³ represents a C₁ -C₁₀ alkyl group, aphenyl group, a phenyl group having at least one substituent selectedfrom the group consisting of substituents (g) or a heterocyclic groupHet, as defined above, or a C₁ -C₃ alkyl group substituted by a singlesubstituent selected from the group consisting of substituents (h); saidsubstituents (f) are selected from the group consisting of phenylgroups, carboxy groups, C₂ -C₆ alkoxycarbonyl groups andbenzyloxycarbonyl groups; said substituents (g) are selected from thegroup consisting of C₁ -C₅ alkyl groups, trifluoromethyl groups, C₁ -C₅alkoxy groups, halogen atoms, nitro groups, amino groups, hydroxy groupsand dialkylamino groups where each alkyl part is C₁ -C₅ ; saidsubstituents (h) are selected from the group consisting ofalkylcarbamoyl groups where the alkyl part is C₁ -C₄, dialkylcarbamoylgroups where each alkyl part is C₁ -C₄, 1-pyrrolidinylcarbonyl groups,piperidinocarbonyl groups and morpholinocarbonyl groups; R⁴ represents aC₁ -C₁₀ alkyl group or a methoxy group; R⁵ represents a hydrogen atom, aC₁ -C₅ alkyl group or a methoxy group; R⁶ and R⁷ are independentlyselected from the group consisting of hydrogen atoms, C₁ -C₅ alkylgroups, C₁ -C₅ alkyl groups substituted by a group of formula--COOR^(8a) where R^(8a) is as defined above, C₂ -C₅ hydroxyalkylgroups, C₁ -C₅ alkyl groups substituted by a C₁ -C₅ alkoxy group, C₂ -C₅alkyl groups substituted by a group of formula --O--CO--R⁵³ where R⁵³ isas defined above, and C₁ -C₃ alkyl groups having a single substituentselected from the group consisting of substituents (h); Ar represents ao-phenylene, m-phenylene or p-phenylene group or a pyridine-diyl groupwhich is attached to the part of said compound of formula (I) of formula--(CH₂)_(n) --O-- at its 2-position and is attached to the --CH₂-thiazolidine group at its 5- or 6-position, said phenylene andpyridine-diyl groups being unsubstituted or having a C₁ -C₃ alkylsubstituent; W represents a group of formula --CH₂ --, >C═O, >CH--OR¹¹or >C═N--OR¹² whereR¹¹ represents a hydrogen atom, a C₁ -C₁₀ alkanoylgroup, a C₃ -C₁₀ alkenoyl group, a substituted C₁ -C₁₀ alkanoyl or C₃-C₁₀ alkenoyl group having at least one substituent selected from thegroup consisting of substituents (f), an arylcarbonyl group wherein thearyl part is a C₆ -C₁₀ carbocyclic aryl group which is unsubstituted orhas at least one substituent selected from the group consisting ofsubstituents (g), a group of formula R¹³ --(CH₂)_(m) --CO-- where R¹³and m are as defined above or a group of formula Het--CO-- where Het isas defined above, and R¹² represents a hydrogen atom, a C₁ -C₅ alkylgroup, a C₁ -C₁₀ alkyl group having at least one substituent selectedfrom the group consisting of substituents (j), a C₁ -C₁₀ alkanoyl group,a C₃ -C₁₀ alkenoyl group, a substituted C₁ -C₁₀ alkanoyl or C₃ -C₁₀alkenoyl group having at least one substituent selected from the groupconsisting of substituents (f), an arylcarbonyl group wherein the arylpart is a C₆ -C₁₀ carbocyclic aryl group which is unsubstituted or hasat least one substituent selected from the group consisting ofsubstituents (g), or said group of formula R¹³ --CH₂)_(m) --CO-- orHet--CO--; and said substituents (j) are selected from the groupconsisting of hydroxy groups, phenyl groups, phenyl groups having atleast one substituent selected from the group consisting of substituents(g), C₂ -C₁₁ alkanoyloxy groups, C₂ -C₁₁ alkanoyloxy groups substitutedby a group of formula --COOR^(8a) where R^(8a) is as defined above, C₃-C₁₁ alkenoyloxy groups substituted by a group of formula --COOR^(8a)where R^(8a) is as defined above, phenylalkenoyloxy groups where thealkenyl part is C₂ -C₁₀ and the phenyl part is unsubstituted or has atleast one substituent selected from the group consisting of substituents(g), benzoyloxy groups, benzoyloxy groups having at least onesubstituent selected from the group consisting of substituents (g),groups of formula --COOR^(8a) where R^(8a) is as defined above,benzyloxycarbonyl groups and groups of formula --COR⁹ R¹⁰ where R⁹ andR¹⁰ are as defined above; U represents(i) where W represents a group offormula --CH₂ --, >C═O, >CH₂ OR¹¹ or >C═N--OR¹², a group of formula--CH₂ --, (ii) with W, a group of formula --CH═CH--, or (iii) where Wrepresents a group of formula >C═O or >C═N--OR¹⁴, in which R¹⁴represents any one of the acyl groups defined for R¹², with R¹ and thecarbon atom to which R¹ is attached, a group of formula --CH═C<.
 3. Acompound as claimed in claim 2, in which:R¹, R², R⁴, R⁵, Ar, W and U aredefined in claim 2; R⁶ and R⁷ both represent hydrogen atoms; R³ and R¹¹are independently selected from the group consisting of hydrogen atoms,C₁ -C₁₀ alkanoyl groups, C₃ -C₁₀ alkenoyl groups, C₁ -C₁₀ alkanoyl or C₃-C₁₀ alkenoyl groups having at least one substituent selected from thegroup consisting of substituents (f) as defined in claim 2, arylcarbonylgroups as defined in claim 2, and groups of formulae R¹³ --(CH₂)_(m)--CO-- and Het--CO-- where R¹³, m and Het are as defined in claim 2; andR¹² represents any one of the groups or atoms defined for R³ and R¹¹ ora C₁ -C₅ alkyl group of a C₁ -C₃ alkyl group having at least onesubstituent selected from the group consisting of substituents (f)defined in claim
 2. 4. A compound as claimed in claim 2, in which:R¹,R², R⁴, R⁵, Ar, W and U are as defined in claim 2; R³, R⁶, R⁷ and R¹²are independently selected from the group consisting of hydrogen atoms,C₁ -C₅ alkyl groups, C₁ -C₅ alkyl groups substituted by a group offormula --COOR^(8a) where R^(8a) is as defined in claim 2, C₂ -C₅hydroxyalkyl groups, C₁ -C₅ alkyl groups substituted by a C₁ -C₅ alkoxygroup, C₂ -C₅ alkyl groups substituted by a group of formula--O--CO--R⁵³ where R⁵³ is as defined in claim 2 and C₁ -C₃ alkyl groupssubstituted by a single substituent selected from the group consistingof substituents (h) as defined in claim 2; and R¹¹ represents a hydrogenatom, an acetyl group or a benzoyl group; or R¹² represents a hydrogenatom, a C₁ -C₅ alkyl group, a C₁ -C₁₀ alkyl group having at least onesubstituent selected from the group consisting of substituents (k), a C₂-C₆ alkanoyl group, a C₂ -C₁₀ alkanoyl group having at least onesubstituent selected from the group consisting of substituents (l), a C₃-C₅ alkenoyl group, a C₃ -C₅ alkenoyl group having at least onesubstituent selected from the group consisting of substituents (l), abenzoyl group, a benzoyl group having at least one substituent selectedfrom the group consisting of substituents (m), a pyridinecarbonyl group,a furoyl group, a thenoyl group or a pyridinecarbonyl, furoyl or thenoylgroup having at least one substituent selected from the group consistingof C₁ -C₅ alkyl groups; said substituents (k) are selected from thegroup consisting of hydroxy groups, phenyl groups, phenyl groups havingat least one substituent selected from the group consisting ofsubstituents (m), C₂ -C₅ alkanoyloxy groups, C₂ -C₁₀ alkanoyloxy or C₃-C₁₀ alkenoyloxy groups substituted by a group of formula --COOR^(8a)where R^(8a) is as defined in claim 2, C₃ -C₁₀ alkenoyloxy groupssubstituted by a phenyl group where the phenyl group is unsubstituted orhas at least one substituent selected from the group consisting ofsubstituents (m), benzoyloxy groups, benzoyloxy groups having at leastone substituent selected from the group consisting of substituents (m),groups of formula --COOR^(8a) where R^(8a) is as defined in claim 2 andsubstituents (h) as defined in claim 2; said substituents (l) areselected from the group consisting of phenyl groups, carboxy groups,alkoxycarbonyl groups where the alkoxy part is C₁ -C₅ andbenzyloxycarbonyl groups; and said substituents (m) are selected fromthe group consisting of C₁ -C₅ alkyl groups, C₁ -C₅ alkoxy groups,halogen atoms and trifluoromethyl groups.
 5. A compound as claimed inclaim 1, in which:R¹ represents an alkyl group selected from the groupconsisting of methyl, ethyl, isobutyl, pentyl, hexyl, 3,3-dimethylbutyl,heptyl, 4,4-dimethylpentyl, octyl, 5,5-dimethylhexyl, nonyl and3,7-dimethyloctyl groups; R² represents a hydrogen atom or a methylgroup; R³ represents a hydrogen atom, a C₁ -C₁₀ alkanoyl group, a C₃-C₁₀ alkenoyl group, a substituted C₁ -C₁₀ alkanoyl or C₃ -C₁₀ alkenoylgroup having at least one substituent selected from the group consistingof substituents (f), a benzoyl group, a benzoyl group having at leastone substituent selected from the group consisting of substituents (n),an aralkanoyl group of formula R¹⁵ --(CH₂)_(m) --CO--where R¹⁵represents a phenyl group or a phenyl group having at least onesubstituent selected from the group consisting of substituents (n), andm is an integer from 1 to 5, a pyridinecarbonyl group, a furoyl group, athenoyl group, a C₁ -C₃ alkyl group, a C₁ -C₃ alkyl group substituted bya group of formula --COOR^(8a) whereR^(8a) represents a hydrogen atom, aC₁ -C₅ alkyl group or an alkoxyalkyl group where both the alkoxy partand the alkyl part are C₁ -C₅, a C₂ -C₃ hydroxyalkyl group, a C₁ -C₅alkyl group substituted by a C₁ -C₅ alkoxy group, a C₂ -C₅ alkyl groupsubstituted by a C₂ -C₄ alkanoyloxy or a benzoyloxy group or a methylgroup having a single substituent selected from the group consisting ofsubstituents (h); said substituents (f) are selected from the groupconsisting of phenyl groups, carboxy groups, C₂ -C₆ alkoxycarbonylgroups and benzyloxycarbonyl groups; said substituents (n) are selectedfrom the group consisting of C₁ -C₅ alkyl groups, C₁ -C₅ alkoxy groupsand halogen atoms; R⁴ represents a C₁ -C₁₀ alkyl group; R⁵ represents ahydrogen atom or a C₁ -C₃ alkyl group; R⁶ and R⁷ are independentlyselected from the group consisting of hydrogen atoms, C₁ -C₃ alkylgroups, C₁ -C₃ alkyl groups substituted by a group of formula--COOR^(8a) where R^(8a) is as defined above, C₂ -C₃ hydroxyalkylgroups, C₁ -C₅ alkyl groups substituted by a C₁ -C₅ alkoxy group, C₂ -C₅alkyl groups substituted by a C₂ -C₄ alkanoyloxy of a benzoyloxy group,and methyl groups substituted by a single substituent selected from thegroup consisting of substituents (h); said substituents (h) are selectedfrom the group consisting of alkylcarbamoyl groups where the alkyl partis C₁ -C₄, dialkylcarbamoyl groups where each alkyl part is C₁ -C₄,1-pyrrolidinylcarbonyl groups, piperidinocarbonyl groups andmorpholinocarbonyl groups; Ar represents a o-phenylene, m-phenylene orp-phenylene group or a pyridine-diyl group which is attached to the partof said compound of formula (I) of formula --(CH₂)_(n) --O-- at its2-position and is attached to the --CH₂ -thiazolidine group at its 5- or6-position, said phenylene and pyridine-diyl groups being unsubstitutedor having a methyl substituent; W represents a group of formula --CH₂--, >C═O, >CH--OR¹¹ or >C═N--OR¹², where:R¹¹ represents a hydrogen atomor any one of the acyl groups defined above for R³ ; and R¹² representsa benzyl group, any one of the groups or atoms defined above for R³, apyridinecarbonyl group or a pyridinecarbonyl group having at least onesubstituent selected from the group consisting of C₁ -C₅ alkyl groups;and U represents(i) where W represents a group of formula --CH₂--, >C═O, >CH--OR¹¹ or >C═N--OR¹² , a group of formula --CH₂ --, (ii)with W, a group of formula --CH═CH--, or (iii) where W represents agroup of formula >C═O, with R¹ and the carbon atom to which R¹ isattached, a group of formula --CH═C<.
 6. A compound as claimed in claim5, in which:R¹, R², R⁴, R⁵, Ar, W and U are as defined in claim 5; R⁶and R⁷ are both hydrogen atoms; R³ and R¹¹ are independently selectedfrom the group consisting of hydrogen atoms, C₁ -C₁₀ alkanoyl groups, C₃-C₁₀ alkenoyl groups, C₁ -C₁₀ alkanoyl or C₃ -C₁₀ alkenoyl groups havingat least one substituent selected from the group consisting ofsubstituents (f) as defined in claim 5, benzoyl groups, benzoyl groupshaving at least one substituent selected from the group consisting ofsubstituents (n) as defined in claim 5, groups of formula R¹⁵--(CH₂)_(m) --CO-- where R¹⁵ and m are as defined in claim 5,pyridinecarbonyl groups, furoyl groups and thenoyl groups; and R¹²represents a hydrogen atom, a methyl group, a benzyl group, at-butoxycarbonylmethyl group or any one of the acyl groups defined abovefor R³ and R¹¹.
 7. A compound as claimed in claim 5, in which:R¹, R²,R⁴, R⁵, Ar, W and U are as defined in claim 5; R³, R⁶ R⁷ areindependently selected from the group consisting of C₁ -C₃ alkyl groups,C₁ -C₃ alkyl groups substituted by a group of formula --COOR^(8a) whereR^(8a) is as defined in claim 5, C₂ -C₃ hydroxyalkyl groups, C₁ -C₅alkyl groups substituted by a C₁ -C₅ alkoxy group, C₂ -C₅ alkyl groupssubstituted by a C₂ -C₄ alkanoyloxy or a benzoyloxy group, and methylgroups having a single substituent selected from the group consisting ofsubstituents (h) as defined in claim 5; R¹¹ represents a hydrogen atom;R¹² represents a hydrogen atom, a C₁ -C₃ alkyl group having at least onesubstituent selected from the group consisting of substituents (o), a C₂-C₄ alkanoyl group, a C₂ -C₄ alkanoyl group substituted by a group offormula --COOR^(8a) where R^(8a) is as defined in claim 5, an acryloylgroup, an acryloyl group having a β-substituent selected from the groupconsisting of substituents (f), a benzoyl group, a benzoyl group havingat least one substituent selected from the group consisting ofsubstituents (q), a pyridinecarbonyl group, a pyridinecarbonyl grouphaving at least one substituent selected from the group consisting of C₁-C₅ alkyl groups or any one of the groups defined above for R³, R⁶ andR⁷ ; said substituents (f) are selected from the group consisting ofphenyl groups, carboxy groups, C₂ -C₆ alkoxycarbonyl groups andbenzyloxycarbonyl groups; and said substituents (o) are selected fromthe group consisting of carboxy groups and alkoxycarbonyl groups wherethe alkoxy part is C₁ -C₅ ; said substituents (q) are selected from thegroup consisting of methyl groups, ethyl groups, methoxy groups andethoxy groups.
 8. A compound as claimed in claim 1 in which:R¹represents an alkyl group selected from the group consisting of methyl,isobutyl, hexyl, heptyl, octyl, nonyl and 3,7-dimethyloctyl groups; R²represents a hydrogen atom or a methyl group; R³ represents a hydrogenatom, a C₁ -C₅ alkanoyl group, C₃ -C₅ alkenoyl group, a cinnamoyl group,a group of formula R¹⁶ OOC(CH₂)_(m) CO--where R¹⁶ represents a hydrogenatom or a C₁ -C₅ alkyl group and m is an integer from 1 to 5, a cis- ortrans- group of formula R¹⁷ OOC.CH═CH--CO--where R¹⁷ represents ahydrogen atom, a C₁ -C₅ alkyl group or a benzyl group, a 2-, 3- or4-pyridinecarbonyl group or a C₁ -C₃ alkyl group substituted by a groupof formula --COOR^(8a) whereR^(8a) represents a hydrogen atom, a C₁ -C₅alkyl group or an alkoxyalkyl group where both the alkoxy part and thealkyl part are C₁ -C₅ ; R⁴ represents an alkyl group selected from thegroup consisting of methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl,octyl, 1,1,3,3-tetramethylbutyl, 1,1-dimethylbutyl and1,1-dimethylpropyl groups; R⁵ represents a hydrogen atom or a methylgroup; R⁶ and R⁷ are independently selected from the group consisting ofhydrogen atoms and C₁ -C₃ alkyl groups substituted by a group of formula--COOR^(8a) where R^(8a) is as defined above; Ar represents ap-phenylene group, a m-phenylene group having a methyl group at theposition ortho to the position of attachment to the group of formula--(CH₂)_(n) --O-- or a pyridine-diyl group attached to said group offormula --(CH₂)_(n) --O-- at the 2-position and to the --CH₂-thiazolidine group at the 5-position; W represents a group of formula--CH₂ --, >C═O, >C═N--OH, >C═N--OCH₂ COOH or >C═N--OCOR¹⁸ where R¹⁸represents a C₁ -C₅ alkyl group; and U represents a group of formula--CH₂ --.
 9. A compound as claimed in claim 8, in which:R¹, R², R⁴, R⁵,Ar and U are as defined in claim 8; R³ represents a hydrogen atom, a C₁-C₅ alkanoyl group, a C₃ -C₅ alkenoyl group, a cinnamoyl group, a groupof formula R¹⁶ OOC(CH₂)_(m) CO-- where R¹⁶ and m are as defined in claim8, a cis or trans- group of formula R¹⁷ OOC.CH═CH--CO-- where R¹⁷ is asdefined in claim 8, or a 2-, 3- or 4-pyridinecarbonyl group; R⁶ and R⁷are both hydrogen atoms; W represents a group of formula >C═NOR¹²whereR¹² represents a hydrogen atom, a group of formula --(CH₂)₃COOR^(8a), --CH₂ COOR^(8a), --C(CH₃)₂ COOR^(8a), --COCH₂ CH₂ COOR^(8a)or --CO--CH═CH--COOR^(8a) where R^(8a) is as defined in claim 8, anacetyl group, a cinnamoyl group, a benzoyl group, a pyridinecarbonylgroup or any one of the groups defined above for R³, R⁶ and R⁷ ; and nis 1 or
 2. 10. A compound as claimed in claim 8, in which:R¹, R², R⁴,R⁵, Ar and U are as defined in claim 8; R³, R⁶ and R⁷ are independentlyselected from the group consisting of C₁ -C₃ alkyl groups substituted bya group of formula --COOR^(8a) where R^(8a) is as defined in claim 8; Wrepresents a group of formula >CH₂, >C═O or >C═NOR¹² ;R¹² represents ahydrogen atom, a group of formula --(CH₂)₃ COOR^(8a), --CH₂ COOR^(8a),--C(CH₃)₂ COOR^(8a), --COCH₂ CH₂ COOR^(8a) or --CO--CH═CH--COOR^(8a)where R^(8a) is as defined in claim 8, an acetyl group, a cinnamoylgroup, a benzoyl group, a pyridinecarbonyl group or any one of thegroups defined above for R³, R⁶ and R⁷ ; and n is 1 or
 2. 11. A compoundas claimed in claim 2, in which:R¹ represents an alkyl group selectedfrom the group consisting of methyl, isobutyl, hexyl, heptyl, octyl,nonyl and 3,7-dimethyloctyl groups; R² represents a hydrogen atom or amethyl group; R³ represents a hydrogen atom, a C₁ -C₁₀ alkanoyl group, aC₃ -C₁₀ alkenoyl group, a C₁ -C₁₀ alkanoyl or C₃ -C₁₀ alkenoyl grouphaving at least one substituent selected from the group consisting ofsubstituents (f) as defined in claim 2, an arylcarbonyl group as definedin claim 2, a group of formula R¹³ --(CH₂)_(m) --CO-- or Het--CO-- whereR¹³, m and Het are as defined in claim 2 or a C₁ -C₃ alkyl groupsubstituted by a group of formula --COOR^(8a) where R^(8a) is as definedin claim 2; R⁴ represents an alkyl group selected from the groupconsisting of methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl,octyl, 1,1,3,3-tetramethylbutyl, 1,1-dimethylbutyl and1,1-dimethylpropyl groups; R⁵ represents a hydrogen atom or a methylgroup; R⁶ represents a C₁ -C₃ alkyl group substituted by a group offormula --COOR^(8a) where R^(8a) is as defined in claim 2; R⁷ representsa hydrogen atom or a C₁ -C₃ alkyl group substituted by a group offormula --COOR^(8a) where R^(8a) is as defined in claim 2; Ar representsa p-phenylene group, a m-phenylene group having a methyl group at theposition ortho to the position of attachment to the group of formula--(CH₂)_(n) --O-- or a pyridine-diyl group attached to said group offormula --(CH₂)_(n) --O-- at the 2-position and to the --CH₂-thiazolidine group at the 5-position; W represents a group of formula>CH₂, >C═O or >C═NOR¹², whereR¹² represents a hydrogen atom, a group offormula --(CH₂)₃ COOR^(8a), --CH₂ COOR^(8a), --C(CH₃)₂ COOR^(8a),--COCH₂ CH₂ COOR^(8a) or --CO--CH═CH--COOR^(8a) where R^(8a) is asdefined in claim 2, an acetyl group, a cinnamoyl group, a benzoyl group,a pyridinecarbonyl group or a C₁ -C₃ alkyl group substituted by a groupof formula --COOR^(8a) where R^(8a) is as defined in claim 2; Urepresents a group of formula --CH₂ --; and n is 1 or
 2. 12. A compoundas claimed in claim 2, in which:R¹ represents an alkyl group selectedfrom the group consisting of hexyl, heptyl, octyl, nonyl and3,7-dimethyloctyl groups; R² represents a hydrogen atom or a methylgroup; R³ represents a hydrogen atom, a C₁ -C₅ alkanoyl group, C₃ -C₅alkenoyl group, a cinnamoyl group, a group of formula R¹⁶ OOC(CH₂)_(m)CO--where R¹⁴ represents a hydrogen atom or a C₁ -C₅ alkyl group and mis an integer from 1 to 5, a cis- or trans- group of formula R¹⁷OOC.CH═CH--CO--where R¹⁷ represents a hydrogen atom, C₁ -C₅ alkyl groupor a benzyl group, a 2-, 3- or 4-pyridinecarbonyl group or a C₁ -C₃alkyl group substituted by a group of formula --COOR^(8a) where R^(8a)is as defined in claim 2; R⁴ represents an alkyl group selected from thegroup consisting of methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl,octyl, 1,1,3,3-tetramethylbutyl, 1,1-dimethylbutyl and1,1-dimethylpropyl groups; R⁵ represents a hydrogen atom or a methylgroup; R⁶ and R⁷ are independently selected from the group consisting ofhydrogen atoms and C₁ -C₃ alkyl groups substituted by a group of formula--COOR^(8a) where R^(8a) is as defined in claim 2; Ar represents ap-phenylene group, a m-phenylene group having a methyl group at theposition ortho to the position of attachment to the group of formula--(CH₂)_(n) --O-- or a pyridine-diyl group attached to said group offormula --(CH₂)_(n) --O-- at the 2-position and to the --CH₂-thiazolidine group at the 5-position; W represents a group of formula--CH₂ --, >C═O or >C═N--OR¹², whereR¹² represents a hydrogen atom, agroup of formula --(CH₂)₃ COOR^(8a), --CH₂ COOR^(8a), --C(CH₃)₂COOR^(8a), --COCH₂ CH₂ COOR^(8a) or --CO--CH═CH--COOR^(8a) where R^(8a)is as defined in claim 2, an acetyl group, a cinnamoyl group, a benzoylgroup, a pyridinecarbonyl group, a C₁ -C₅ alkyl group, a C₁ -C₅ alkylgroup substituted by a phenyl group where the phenyl group isunsubstituted or has at least one substituent selected from the groupconsisting of substituents (n), or any one of the groups defined abovefor R³, R⁶ and R⁷ ; said substituents (n) are selected from the groupconsisting of C₁ -C₅ alkyl groups, C₁ -C₅ alkoxy groups and halogenatoms; and U represents a group of formula --CH₂ --.
 13. A compound asclaimed in claim 2, in which:R¹ represents an alkyl group selected fromthe group consisting of methyl, isobutyl, hexyl, heptyl, octyl, nonyland 3,7-dimethyloctyl groups; R² represents a hydrogen atom or a methylgroup; R³ represents a hydrogen atom, a C₁ -C₅ alkanoyl group, C₃ -C₅alkenoyl group, a cinnamoyl group, a group of formula R¹⁶ OOC(CH₂)_(m)CO--where R¹⁶ represents a hydrogen atom or a C₁ -C₅ alkyl group and mis an integer from 1 to 5, a cis- or trans- group of formula R¹⁷OOC.CH═CH--CO--where R¹⁷ represents a hydrogen atom, a C₁ -C₅ alkylgroup of a benzyl group, a 2-, 3- or 4-pyridinecarbonyl group or a C₁-C₃ alkyl group substituted by a group of formula --COOR^(8a) whereR^(8a) is as defined in claim 2; R⁴ represents an alkyl group selectedfrom the group consisting of hexyl, heptyl, octyl,1,1,3,3-tetramethylbutyl, 1,1-dimethylbutyl and 1,1-dimethylpropylgroups; R⁵ represents a hydrogen atom or a methyl group; R⁶ and R⁷ areindependently selected from the group consisting of hydrogen atoms andC₁ -C₃ alkyl groups substituted by a group of formula --COOR^(8a) whereR^(8a) is as defined in claim 2; Ar represents a p-phenylene group, am-phenylene group having a methyl group at the position ortho to theposition of attachment to the group of formula --(CH₂)_(n) --O-- or apyridine-diyl group attached to said group of formula --(CH₂)_(n) --O--at the 2-position and to the --CH₂ -thiazolidine group at the5-position; W represents a group of formula --CH₂ --, >C═O or >C═N--OR¹²whereR¹² represents a hydrogen atom, a group of formula --(CH₂)₃COOR^(8a), --CH₂ COOR^(8a), --C(CH₃)₂ COOR^(8a), --COCH₂ CH₂ COOR^(8a)or --CO--CH═CH--COOR^(8a) where R^(8a) is as defined in claim 2, anacetyl group, a cinnamoyl group, a benzoyl group, a pyridinecarbonylgroup, a C₁ -C₅ alkyl group, a C₁ -C₅ alkyl group substituted by aphenyl group where the phenyl group is unsubstituted or has at least onesubstituent selected from the group consisting of substituents (n), orany one of the groups defined above for R³, R⁶ and R⁷ ; saidsubstituents (n) are selected from the group consisting of C₁ -C₅ alkylgroups, C₁ -C₅ alkoxy groups and halogen atoms; and U represents a groupof formula --CH₂ --.
 14. A compound as claimed in claim 2, in which:R¹represents an alkyl group selected from the group consisting of methyl,isobutyl, hexyl, heptyl, octyl, nonyl and 3,7-dimethyloctyl groups; R²represents a hydrogen atom or a methyl group; R³ represents C₁ -C₃ alkylgroup substituted by a group of formula --COOR^(8a), where R^(8a) is asdefined in claim 2; R⁴ represents an alkyl group selected from the groupconsisting of methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl,octyl, 1,1,3,3-tetramethylbutyl, 1,1-dimethylbutyl and1,1-dimethylpropyl groups; R⁵ represents a hydrogen atom or a methylgroup; R⁶ and R⁷ are both hydrogen atoms; Ar represents a p-phenylenegroup, a m-phenylene group having a methyl group at the position orthoto the position of attachment to the group of formula --(CH₂)_(n) --O--or a pyridine-diyl group attached to said group of formula --(CH₂)_(n)--O-- at the 2-position and to the --CH₂ -thiazolidine group at the5-position; W represents a group of formula --CH₂ --, >C═O, >C═N--OH, or>C═N--O--(C₁ -C₃ alkyl)--COOR^(8a) where R^(8a) is as defined in claim2; U represents a group of formula --CH₂ --; and n is 1 or
 2. 15. Acompound as claimed in claim 2, in which:R¹ represents an alkyl groupselected from the group consisting of methyl, isobutyl, hexyl, heptyl,octyl, nonyl and 3,7-dimethyloctyl groups; R² represents a hydrogen atomor a methyl group; R³ represents --CH₂ --COO(C₁ -C₅ alkyl) group; R⁴represents an alkyl group selected from the group consisting of methyl,ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl,1,1,3,3-tetramethylbutyl, 1,1-dimethylbutyl and 1,1-dimethylpropylgroups; R⁵ represents a hydrogen atom or a methyl group; R⁶ and R⁷ areboth hydrogen atoms; Ar represents a p-phenylene group, a m-phenylenegroup having a methyl group at the position ortho to the position ofattachment to the group of formula --(CH₂)_(n) --O-- or a pyridine-diylgroup attached to said group of formula --(CH₂)_(n) --O-- at the2-position and to the --CH₂ -thiazolidine group at the 5-position; Wrepresents a group of formula --CH₂ --, >C═O, >C═N--OH, or >C═N--O--(C₁-C₃ alkyl)--COO(C₁ -C₅ alkyl); U represents a group of formula --CH₂ --;and n is 1 or
 2. 16. The compound as claimed in claim 1, which is5-[4-(6-Hydroxy-5,7,8-trimethyl-2-octylchroman-2-ylmethoxy)benzyl]thiazolidine-2,4-dioneand pharmaceutically acceptable salts thereof.
 17. The compound asclaimed in claim 1, which is5-{4-[6-Hydroxy-4-(E)-hydroxyimino-2,5,7,8-tetramethylchroman-2-ylmethoxy]benzyl}thiazolidine-2,4-dioneand pharmaceutically acceptable salts thereof.
 18. The compound asclaimed in claim 1, which5-{4-[6-Acetoxy-4-(E)-acetoxyimino-2,5,7,8-tetramethylchroman-2-ylmethoxy]benzyl}thiazolidine-2,4-dioneand pharmaceutically acceptable salts thereof.
 19. The compound asclaimed in claim 1, which isα-{5-[4-(6-Carboxymethoxy-2,5,7,8-tetramethyl-4-oxochroman-2-ylmethoxy)benzyl]-2,4-dioxothiazolidin-3-yl}aceticacid and pharmaceutically acceptable salts thereof.
 20. The compound asclaimed in claim 1, which isα-{5-[4-(6-Carboxymethoxy-4-hydroxyimino-2,5,7,8-tetramethylchroman-2-ylmethoxy)benzyl]-2,4-dioxothiazolidin-3-yl}aceticacid and pharmaceutically acceptable salts thereof.
 21. The compound asclaimed in claim 1, which isα,α'-{5-[4-(6-Carboxymethoxy-4-hydroxyimino-2,5,7,8-tetramethylchroman-2-ylmethoxy)benzyl]-2,4-dioxothiazolidine-3,5-diyl}diaceticacid and pharmaceutically acceptable salts thereof.
 22. A pharmaceuticalcomposition for the treatment of hyperlipaemia or hyperglycaemia,comprising an effective amount of an active compound in combination witha pharmaceutically acceptable carrier or diluent, wherein the activecompound is selected from the group consisting of compounds of formula(1): ##STR620## in which: R¹ represents a hydrogen atom, a C₁ -C₁₀ alkylgroup or a C₇ -C₁₃ aralkyl group;R² represents a hydrogen atom or a C₁-C₅ alkyl group; R³ represents a hydrogen atom, a C₁ -C₂₃ alkanoylgroup, a C₃ -C₂₃ alkenoyl group, a C₃ -C₂₃ alkynoyl group, a substitutedC₁ -C₂₃ alkanoyl, C₃ -C₂₃ alkenoyl or C₃ -C₂₃ alkynoyl group having atleast one substituent selected from the group consisting of substituents(a), an aromatic acyl group selected from the group consisting ofbenzoyl and naphthoyl, a 5 to 8-membered heterocyclic acyl group having1 to 3 hetero atoms of N, S or O, a group of formula --SO₃ R⁸ where R⁸represents a hydrogen atom, an aralkyl group where the alkyl part is C₁-C₃ alkyl, a C₁ -C₅ alkyl group or a C₁ -C₅ alkyl group having at leastone substituent selected from the group consisting of hydroxy groups andC₁ -C₅ alkoxy groups, a C₁ -C₁₀ alkyl group or a substituted C₁ -C₁₀alkyl group having at least one substituent selected from the groupconsisting of substituents (b); R⁴ represents a hydrogen atom, a C₁ -C₁₀alkyl group or a C₁ -C₅ alkoxy group; R⁵ represents a hydrogen atom, aC₁ -C₅ alkyl group or a C₁ -C₅ alkoxy group; R⁶ and R⁷ are independentlyselected for the group consisting of hydrogen atoms, C₁ -C₁₀ alkylgroups and substituted C₁ -C₁₀ alkyl groups having at least onesubstituent selected from the group consisting of substituents (b); Aris a divalent group selected from the group consisting of divalentcarbocyclic aromatic groups, and divalent heterocyclic aromatic groupsformed from a pyridine, furan, thiophene or pyrrole ring; W represents a--CH₂ -- group, a >C═O group, a group of formula >CH--OR¹¹ where R¹¹represents a hydrogen atom, a C₁ -C₂₃ alkanoyl group, a C₃ -C₂₃ alkenoylgroup, a C₃ -C₂₃ alkynoyl group, a substituted C₁ -C₂₃ alkanoyl, C₃ -C₂₃alkenoyl or C₃ -C₂₃ alkynoyl group having at least one substituentselected from the group consisting of substituents (a), an aromatic acylgroup selected from the group consisting of benzoyl and napthoyl, a 5-8membered heterocyclia acyl having 1 to 3 heteroatoms of N, S, or O, A C₁-C₁₀ alkyl group or a substituted C₁ -C₁₀ alkyl group having at leastone substituent selected from the group consisting of substituents (b),or a group of formula >C═N--O--R¹² in which R¹² represents a hydrogenatom, a C₁ -C₁₀ alkyl group, a C₁ -C₁₀ alkyl group having at least onesubstituent selected from the group consisting of substituents (b), a C₁-C₂₃ alkanoyl group, a C₃ -C₂₃ alkenoyl group, a C₃ -C₂₃ alkynoyl group,a substituted C₁ -C₂₃ alkanoyl, C₃ -C₂₃ alkenoyl or C₃ -C₂₃ alkynoylgroup having at least one substituent selected from the group consistingof substituents (a), an aromatic acyl group selected from the groupconsisting of benzoyl and naphthoyl or a heterocyclic acyl group having1 to 3 heteroatoms of N, S or O; U represents a --CH₂ -- group; or W andU together represent a group of formula --CH═CH--; or when W representsa carbonyl group of said group of formula >C═N--OR¹², U, R¹ and thecarbon atom to which R¹ is attached together represent a group offormula --CH═C<; n is an integer of from 1 to 3; said aryl groups andthe aryl parts of said aralkyl, aralkyloxycarbonyl, and aromatic acyloxybeing C₆ -C₁₀ carbocyclic aryl groups which are unsubstituted or have atleast one substituent selected from the group consisting of substituents(c); said heterocyclic groups, heterocyclic parts of said heterocyclicacyl and acyloxy groups have from 5 to 10 ring atoms, of which 1 to 5are hetero-atoms selected from the group consisting of nitrogen, oxygenand sulfur hetero-atoms, said heterocyclic groups being unsubstituted orhaving at least one substituent selected from the group consisting ofsubstituents (d); said substituents (a) being selected from the groupconsisting of aryl groups, carboxy groups, C₂ -C₆ alkoxycarbonyl groupsand aralkyloxycarbonyl groups; said substituents (b) being selected fromthe group consisting of hydroxy groups, C₁ -C₅ alkoxy groups, arylgroups, C₁ -C₂₃ alkanoyloxy groups, C₃ -C₂₃ alkenoyloxy groups, C₃ -C₂₃alkynoyloxy groups, substituted C₁ -C₂₃ alkanoyloxy, C₃ -C₂₃ alkenoyloxyor C₃ -C₂₃ alkynoyloxy groups having at least one substituent selectedfrom the group consisting of substituents (a), aromatic acyloxy groups,heterocyclic acyloxy groups, groups of formula --COOR⁸ where R⁸ is asdefined above and groups of formula --CONR⁹ R¹⁰ whereR⁹ and R¹⁰ areindependently selected from the group consisting of hydrogen atoms andC₁ -C₅ alkyl groups or R⁹ and R¹⁰, together with the nitrogen atom towhich they are attached, represent a heterocyclic group having from 5 to7 ring atoms of which from 1 to 3 atoms, including said nitrogen atom,are hetero-atoms selected from the group consisting of nitrogen, oxygenand sulfur hetero-atoms, said heterocyclic group being unsubstituted,or, where said ring atoms include an additional nitrogen hetero-atom,said additional nitrogen atom being unsubstituted or having a singlesubstituent selected from the group consisting of substituents (e); saidsubstituents (c) being selected from the group consisting of C₁ -C₅alkyl groups, C₁ -C₅ alkoxy groups, C₁ -C₅ alkyl groups having at leastone halogen substituent, halogen atoms, amino groups, C₁ -C₅ alkylaminogroups, dialkylamino groups in which each alkyl part is C₁ -C₅, nitrogroups, cyano groups, groups of formula --CONR₂ where R represents a C₁-C₅ alkyl group or an aryl group and hydroxy groups; and saidsubstituents (d) being selected from the group consisting of C₁ -C₅alkyl groups, C₁ -C₅ alkoxy groups and doubly bonded oxygen atoms; saidsubstituents (e) being selected from the group consisting of C₁ -C₅alkyl groups, C₁ -C₅ alkanoyl groups, C₃ -C₅ alkenoykl groups and C₃ -C₅alkynoyl groups; provided that: (α) where: R³ represents said hydrogenatom, an unsubstituted C₁ -C₆ alkanoyl group, an unsubstituted C₃ -C₆alkenoyl group, an unsubstituted C₃ -C₆ alkynoyl group, said aromaticacyl group, said heterocyclic acyl group, an aralkanoyl group or anaralkenoyl group; and R⁶ and R⁷ both represent hydrogen atoms; and Arrepresents a p-phenylene group; and W represents a group of formula>CH₂, >C═O or >CH--OR^(11x) (wherein R^(11x) represents a hydrogen atom,an unsubstituted C₁ -C₆ alkanoyl group, an unsubstituted C₃ -C₆ alkenoylgroup, an unsubstituted C₃ -C₆ alkynoyl group, said aromatic acyl group,said heterocyclic acyl group, an aralkanoyl group or an aralkenoylgroup); and U represents said group of formula >CH₂, then(i) when R¹represents a hydrogen atom or a C₁ -C₅ alkyl group, R⁴ represents a C₆-C₁₀ alkyl group, and (ii) when R⁴ represents a hydrogen atom, a C₁ -C₅alkyl group or a C₁ -C₅ alkoxy group, R¹ represents a C₆ -C₁₀ alkylgroup or said C₇ -C₁₃ aralkyl group; or (β) where: R¹ and R² areindependently selected from the group consisting of hydrogen atoms andC₁ -C₅ alkyl groups; and R⁴ and R⁵ are independently selected from thegroup consisting of hydrogen atoms, C₁ -C₅ alkyl groups and C₁ -C₅alkoxy groups; and Ar represents a p-phenylene group; and W is a groupof formula >CH₂, >C═O or >CH--OR^(11x) (where R^(11x) is as definedabove); and U represents said group of formula >CH₂ ; and n is aninteger from 1 to 3, then at least one of R³, R⁶ and R⁷ represents saidalkyl or substituted alkyl group; and pharmaceutically acceptable saltsthereof.
 23. A composition as claimed in claim 22, in which:R¹represents a hydrogen atom or a C₁ -C₁₀ alkyl group; R² represents ahydrogen atom or a C₁ -C₃ alkyl group; R³ represents a hydrogen atom, asulfo group, a C₁ -C₁₀ alkanoyl group, a C₃ -C₁₀ alkenoyl group, asubstituted C₁ -C₁₀ alkanoyl or C₃ -C₁₀ alkenoyl group having at leastone substituent selected from the group consisting of substituents (f),an arylcarbonyl group wherein the aryl part is a C₆ -C₁₀ carbocyclicaryl group which is unsubstituted or has at least one substituentselected from the group consisting of substituents (g), a group offormula R¹³ --(CH₂)_(m) --CO--, whereR¹³ represents a phenyl group or aphenyl group having at least one substituent selected from the groupconsisting of substituents (g), and m is an integer from 1 to 5, a groupof formula Het--CO--, whereHet represents a heterocyclic group having 5to 6 ring atoms, of which from 1 to 3 are hetero-atoms selected from thegroup consisting of nitrogen, oxygen and sulfur hetero-atoms, saidheterocyclic group being unsubstituted or having at least onesubstituent selected from the group consisting of C₁ -C₅ alkyl groups, aC₁ -C₅ alkyl group, a C₁ -C₅ alkyl group substituted by a group offormula --COOR^(8a), whereR^(8a) represents a hydrogen atom, a C₁ -C₅alkyl group or an alkoxyalkyl group where both the alkoxy part and thealkyl part are C₁ -C₅, a C₂ -C₅ hydroxyalkyl group, a C₂ -C₅ alkyl groupsubstituted by a group of formula --O--CO--R⁵³, whereR⁵³ represents a C₁-C₁₀ alkyl group, a phenyl group, a phenyl group having at least onesubstituent selected from the group consisting of substituents (g) or aheterocyclic group Het, as defined above, or a C₁ -C₃ alkyl groupsubstituted by a single substituent selected from the group consistingof substituents (h); said substituents (f) are selected from the groupconsisting of phenyl groups, carboxy groups, C₂ -C₆ alkoxycarbonylgroups and benzyloxycarbonyl groups; said substituents (g) are selectedfrom the group consisting of C₁ -C₅ alkyl groups, trifluoromethylgroups, C₁ -C₅ alkoxy groups, halogen atoms, nitro groups, amino groups,hydroxy groups and dialkylamino groups where each alkyl part is C₁ -C₅ ;said substituents (h) are selected from the group consisting ofalkylcarbamoyl groups where the alkyl part is C₁ -C₄, dialkylcarbamoylgroups where each alkyl part is C₁ -C₄, 1-pyrrolidinylcarbonyl groups,piperidinocarbonyl groups and morpholinocarbonyl groups; R⁴ represents aC₁ -C₁₀ alkyl group or a methoxy group; R⁵ represents a hydrogen atom, aC₁ -C₅ alkyl group or a methoxy group; R⁶ and R⁷ are independentlyselected from the group consisting of hydrogen atoms, C₁ -C₅ alkylgroups, C₁ -C₅ alkyl groups substituted by a group of formula--COOR^(8a) where R^(8a) is as defined above, C₂ -C₅ hydroxyalkylgroups, C₁ -C₅ alkyl groups substituted by a C₁ -C₅ alkoxy group, C₂ -C₅alkyl groups substituted by a group of formula --O--CO--R⁵³ where R⁵³ isas defined above, and C₁ -C₃ alkyl groups having a single substituentselected from the group consisting of substituents (h); Ar represents ao-phenylene, m-phenylene or p-phenylene group or a pyridine-diyl groupwhich is attached to the part of said compound of formula (I) of formula--(CH₂)_(n) --O-- at its 2-position and is attached to the --CH₂-thiazolidine group at its 5- or 6-position, said phenylene andpyridine-diyl groups being unsubstituted or having a C₁ -C₃ alkylsubstituent; W represents a group of formula --CH₂ --, >C═O, >CH--OR¹¹or >C═N--OR¹² whereR¹¹ represents a hydrogen atom, a C₁ -C₁₀ alkanoylgroup, a C₃ -C₁₀ alkenoyl group, a substituted C₁ -C₁₀ alkanoyl or C₃-C₁₀ alkenoyl group having at least one substituent selected from thegroup consisting of substituents (f), an arylcarbonyl group wherein thearyl part is a C₆ -C₁₀ carbocyclic aryl group which is unsubstituted orhas at least one substituent selected from the group consisting ofsubstituents (g), a group of formula R¹³ --(CH₂)_(m) --CO-- where R¹³and m are as defined above or a group of formula Het--CO-- where Het isas defined above, and R¹² represents a hydrogen atom, a C₁ -C₅ alkylgroup, a C₁ -C₁₀ alkyl group having at least one substituent selectedfrom the group consisting of substituents (j), a C₁ -C₁₀ alkanoyl group,a C₃ -C₁₀ alkenoyl group, a substituted C₁ -C₁₀ alkanoyl or C₃ -C₁₀alkenoyl group having at least one substituent selected from the groupconsisting of substituents (f), an arylcarbonyl group wherein the arylpart is a C₆ -C₁₀ carbocyclic aryl group which is unsubstituted or hasat least one substituent selected from the group consisting ofsubstituents (g), or said group of formula R¹³ --(CH₂)_(m) --CO-- orHet--CO--; and said substituents (j) are selected from the groupconsisting of hydroxy groups, phenyl groups, phenyl groups having atleast one substituent selected from the group consisting of substituents(g), C₂ -C₁₁ alkanoyloxy groups, C₂ -C₁₁ alkanoyloxy groups substitutedby a group of formula --COOR^(8a) where R^(8a) is as defined above, C₃-C₁₁ alkenoyloxy groups substituted by a group of formula --COOR^(8a)where R^(8a) is as defined above, phenylalkenoyloxy groups where thealkenyl part is C₂ -C₁₀ and the phenyl part is unsubstituted or has atleast one substituent selected from the group consisting of substituents(g), benzoyloxy groups, benzoyloxy groups having at least onesubstituent selected from the group consisting of substituents (g),groups of formula --COOR^(8a) where R^(8a) is as defined above,benzyloxycarbonyl groups and groups of formula --COR⁹ R¹⁰ where R⁹ andR¹⁰ are as defined above; U represents(i) where W represents a group offormula --CH₂ --, >C═O, >CH₂ OR¹¹ or >C═N--OR¹², a group of formula--CH₂ --, (ii) with W, a group of formula --CH═CH--, or (iii) where Wrepresents a group of formula >C═O or >C═N--OR¹⁴, in which R¹⁴represents any one of the acyl groups defined for R¹², with R¹ and thecarbon atom to which R¹ is attached, a group of formula --CH═C<.
 24. Acomposition as claimed in claim 23, in which:R¹, R², R⁴, R⁵, Ar, W and Uare as defined in claim 23; R⁶ and R⁷ both represent hydrogen atoms; R³and R¹¹ are independently selected from the group consisting of hydrogenatoms, C₁ -C₁₀ alkanoyl groups, C₃ -C₁₀ alkenoyl groups, C₁ -C₁₀alkanoyl or C₃ -C₁₀ alkenoyl groups having at least one substituentselected from the group consisting of substituents (f) as defined inclaim 23, arylcarbonyl groups as defined in claim 23, and groups offormulae R¹³ --(CH₂)_(m) --CO-- and Het--CO-- where R¹³, m and Het areas defined in claim 23; and R¹² represents any one of the groups oratoms defined for R³ and R¹¹ or a C₁ -C₅ alkyl group or a C₁ -C₃ alkylgroup having at least one substituent selected from the group consistingof substituents (f) defined in claim
 23. 25. A composition as claimed inclaim 23, in which:R¹, R², R⁴, R⁵, Ar, W and U are as defined in claim23; R³, R⁶, R⁷ and R¹² are independently selected from the groupconsisting of hydrogen atom, C₁ -C₅ alkyl groups, C₁ -C₅ alkyl groupssubstituted by a group of formula --COOR^(8a) where R^(8a) is as definedin claim 23, C₂ -C₅ hydroxyalkyl groups, C₁ -C₅ alkyl groups substitutedby a C₁ -C₅ alkoxy group, C₂ -C₅ alkyl groups substituted by a group offormula --O--CO--R⁵³ where R⁵³ is as defined in claim 23 and C₁ -C₃alkyl groups substituted by a single substituent selected from the groupconsisting of substituents (h) as defined in claim 23; and R¹¹represents a hydrogen atom, an acetyl group or a benzoyl group; R¹²represents a hydrogen atom, a C₁ -C₅ alkyl group, a C₁ -C₁₀ alkly grouphaving at least one substituent selected from the group consisting ofsubstituents (k), a C₂ -C₆ alkanoyl group, a C₂ -C₁₀ alkanoyl grouphaving at least one substituent selected from the group consisting ofsubstituents (l), a C₃ -C₅ alkenoyl group, a C₃ -C₅ alkenoyl grouphaving at least one substituent selected from the group consisting ofsubstituents (l), a benzoyl group, a benzoyl group having at least onesubstituent selected from the group consisting of substituents (m), apyridinecarbonyl group, a furoyl group, a thenoyl group or apyridinecarbonyl, furoyl or thenoyl group having at least onesubstituent selected from the group consisting of C₁ -C₅ alkyl groups;said substituents (k) are selected from the group consisting of hydroxygroups, phenyl groups, phenyl groups having at least one substituentselected from the group consisting of substituents (m), C₂ -C₅alkanoyloxy groups, C₂ -C₁₀ alkanoyloxy or C₃ -C₁₀ alkenoyloxy groupssubstituted by a group of formula --COOR^(8a) where R^(8a) is as definedin claim 23, C₃ -C₁₀ alkenoyloxy groups substituted by a phenyl groupwhere the phenyl group is unsubstituted or has at least one substituentselected from the group consisting of substituents (m), benzoyloxygroups, benzoyloxy groups having at least one substituent selected fromthe group consisting of substituents (m), groups of formula --COOR^(8a)where R^(8a) is as defined in claim 23 and substituents (h) as definedin claim 23; said substituents (l) are selected from the groupconsisting of phenyl groups, carboxy groups, alkoxycarbonyl groups wherethe alkoxy part is C₁ -C₅ and benzyloxycarbonyl groups; and saidsubstituents (m) are selected from the group consisting of C₁ -C₅ alkylgroups, C₁ -C₅ alkoxy groups, halogen atoms and trifluoromethyl groups.26. A composition as claimed in claim 22, in which:R¹ represents analkyl group selected from the group consisting of methyl, ethyl,isobutyl, pentyl, hexyl, 3,3-dimethylbutyl, heptyl, 4,4-dimethylpentyl,octyl, 5,5-dimethylhexyl, nonyl and 3,7-dimethyloctyl groups; R²represents a hydrogen atom or a methyl group; R³ represents a hydrogenatom, a C₁ -C₁₀ alkanoyl group, a C₃ -C₁₀ alkenoyl group, a substitutedC₁ -C₁₀ alkanoyl or C₃ -C₁₀ alkenoyl group having at least onesubstituent selected from the group consisting of substituents (f), abenzoyl group, a benzoyl group having at least one substituent selectedfrom the group consisting of substituents (n), an aralkanoyl group offormula R¹⁵ --(CH₂)_(m) --CO--where R¹⁵ represents a phenyl group or aphenyl group having at least one substituent selected from the groupconsisting of substituents (n), and m is an integer from 1 to 5, apyridinecarbonyl group, a furoyl group, a thenoyl group, a C₁ -C₃ alkylgroup, a C₁ -C₃ alkyl group substituted by a group of formula--COOR^(8a) whereR^(8a) represents a hydrogen atom, a C₁ -C₅ alkyl groupor an alkoxyalkyl group where both the alkoxy part and the alkyl partare C₁ -C₅, a C₂ -C₃ hydroxyalkyl group, a C₁ -C₅ alkyl groupsubstituted by a C₁ -C₅ alkoxy group, a C₂ -C₅ alkyl group substitutedby a C₂ -C₄ alkanoyloxy or a benzoyloxy group or a methyl group having asingle substituent selected from the group consisting of substituents(h); said substituents (f) are selected from the group consisting ofphenyl groups, carboxy groups, C₂ -C₆ alkoxycarbonyl groups andbenzyloxycarbonyl groups; said substituents (n) are selected from thegroup consisting of C₁ -C₅ alkyl groups, C₁ -C₅ alkoxy groups andhalogen atoms; R⁴ represents a C₁ -C₁₀ alkyl group; R⁵ represents ahydrogen atom or a C₁ -C₃ alkyl group; R⁶ and R⁷ are independentlyselected from the group consisting of hydrogen atoms, C₁ -C₃ alkylgroups, C₁ -C₃ alkyl groups substituted by a group of formula--COOR^(8a) where R^(8a) is as defined above, C₂ -C₃ hydroxyalkylgroups, C₁ -C₅ alkyl groups substituted by a C₁ -C₅ alkoxy group, C₂ -C₅alkyl groups substituted by a C₂ -C₄ alkanoyloxy or a benzoyloxy group,and methyl groups substituted by a single substituent selected from thegroup consisting of substituents (h); said substituents (h) are selectedfrom the group consisting of alkylcarbamoyl groups where the alkyl partis C₁ -C₄, dialkylcarbamoyl groups where each alkyl part is C₁ -C₄,1-pyrrolidinylcarbonyl groups, piperidinocarbonyl groups andmorpholinocarbonyl groups; Ar represents a o-phenylene, m-phenylene orp-phenylene group or a pyridine-diyl group which is attached to the partof said compound of formula (I) of formula --(CH₂)_(n) --O-- at its2-position and is attached to the --CH₂ -thiazolidine group at its 5- or6-position, said phenylene and pyridine-diyl groups being unsubstitutedor having a methyl substituent; W represents a group of formula --CH₂--, >C═O, >CH--OR¹¹ or >C═N--OR¹², where:R¹¹ represents a hydrogen atomor any one of the acyl groups defined above for R³ ; and R¹² representsa benzyl group, any one of the groups or atoms defined above for R³, apyridinecarbonyl group or a pyridinecarbonyl group having at least onesubstituent selected from the group consisting of C₁ -C₅ alkyl groups;and U represents(i) where W represents a group of formula --CH₂--, >C═O, >CH--OR¹¹ or >C═N--OR¹², a group of formula --CH₂ --, (ii)with W, a group of formula --CH═CH--, or (iii) where W represents agroup of formula >C═O, with R¹ and the carbon atom to which R¹ isattached, a group of formula --CH═C<.
 27. A composition as claimed inclaim 26, in which:R¹, R², R⁴, R⁵, Ar, W and U are as defined in claim26; R⁶ and R⁷ are both hydrogen atoms; R³ and R¹¹ are independentlyselected from the group consisting of hydrogen atoms, C₁ -C₁₀ alkanoylgroups, C₃ -C₁₀ alkenoyl groups, C₁ -C₁₀ alkanoyl or C₃ -C₁₀ alkenoylgroups having at least one substituent selected from the groupconsisting of substituents (f) as defined in claim 26, benzoyl groups,benzoyl groups having at least one substituent selected from the groupconsisting of substituents (n) as defined in claim 26, groups of formulaR¹⁵ --(CH₂)_(m) --CO-- where R¹⁵ and m are as defined in claim 26,pyridinecarbonyl groups, furoyl groups and thenoyl groups; and R¹²represents a hydrogen atom, a methyl group, a benzyl group, at-butoxycarbonylmethyl group or any one of the acyl groups defined abovefor R³ and R¹¹.
 28. A composition as claimed in claim 26, in which:R¹,R², R⁴, R⁵, Ar, W and U are as defined in claim 26; R³, R⁶ and R⁷ areindependently selected from the group consisting of C₁ -C₃ alkyl groups,C₁ -C₃ alkyl groups substituted by a group of formula --COOR^(8a) whereR^(8a) is as defined in claim 26, C₂ -C₃ hydroxyalkyl groups, C₁ -C₅alkyl groups substituted by a C₁ -C₅ alkoxy group, C₂ -C₅ alkyl groupssubstituted by a C₂ -C₄ alkanoyloxy or a benzoyloxy group, and methylgroups having a single substituent selected from the group consisting ofsubstituents (h) as defined in claim 26; R¹¹ represents a hydrogen atom;R¹² represents a hydrogen atom, a C₁ -C₃ alkyl group having at least onesubstituent selected from the group consisting of substituents (o), a C₂-C₄ alkanoyl group, a C₂ -C₄ alkanoyl group substituted by a group offormula --COOR^(8a) where R^(8a) is as defined in claim 26, an acryloylgroup, an acryloyl group having a β-substituent selected from the groupconsisting of substituents (f), a benzoyl group, a benzoyl group havingat least one substituent selected from the group consisting ofsubstituents (q), a pyridinecarbonyl group, a pyridinecarbonyl grouphaving at least one substituent selected from the group consisting of C₁-C₅ alkyl groups or any one of the groups defined above for R³, R⁶ andR⁷ ; said substituents (f) are selected from the group consisting ofphenyl groups, carboxy groups, C₂ -C₆ alkoxycarbonyl groups andbenzyloxycarbonyl groups; and said substituents (o) are selected fromthe group consisting of carboxy groups and alkoxycarbonyl groups wherethe alkoxy part is C₁ -C₅ ; said substituents (g) are selected from thegroup consisting of methyl groups, ethyl groups, methoxy groups andethoxy groups.
 29. A composition as claimed in claim 22 in which:R¹represents an alkyl group selected from the group consisting of methyl,isobutyl, hexyl, heptyl, octyl, nonyl and 3,7-dimethyloctyl groups; R²represents a hydrogen atom or a methyl group; R³ represents a hydrogenatom, a C₁ -C₅ alkanoyl group, C₃ -C₅ alkenoyl group, a cinnamoyl group,a group of formula R¹⁶ OOC(CH₂)_(m) CO--where R¹⁶ represents a hydrogenatom or a C₁ -C₅ alkyl group and m is an integer from 1 to 5, a cis- ortrans- group of formula R¹⁷ OOC.CH═CH--CO--where R¹⁷ represents ahydrogen atom, a C₁ -C₅ alkyl group or a benzyl group, a 2-, 3- or4-pyridinecarbonyl group or a C₁ -C₃ alkyl group substituted by a groupof formula --COOR^(8a) whereR^(8a) represents a hydrogen atom, a C₁ -C₅alkyl group or an alkoxyalkyl group where both the alkoxy part and thealkyl part are C₁ -C₅ ; R⁴ represents an alkyl group selected from thegroup consisting of methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl,octyl, 1,1,3,3-tetramethylbutyl, 1,1-dimethylbutyl and1,1-dimethylpropyl groups; R⁵ represents a hydrogen atom or a methylgroup; R⁶ and R⁷ are independently selected from the group consisting ofhydrogen atoms and C₁ -C₃ alkyl groups substituted by a group of formula--COOR^(8a) where R^(8a) is as defined above; Ar represents ap-phenylene group, a m-phenylene group having a methyl group at theposition ortho to the position of attachment to the group of formula--(CH₂)_(n) --O-- or a pyridine-diyl group attached to said group offormula --(CH₂)_(n) --O-- at the 2-position and to the --CH₂-thiazolidine group at the 5-position; W represents a group of formula--CH₂ --, >C═O, >C═N--OH, >C═N--OCH₂ COOH or >C═N--OCOR¹⁸ where R¹⁸represents a C₁ -C₅ alkyl group; and U represents a group of formula--CH₂ --.
 30. A composition as claimed in claim 29, in which:R¹, R², R⁴,R⁵, Ar and U are as defined in claim 29; R³ represents a hydrogen atom,a C₁ -C₅ alkanoyl group, a C₃ -C₅ alkenoyl group, a cinnamoyl group, agroup of formula R¹⁶ OOC(CH₂)_(m) CO-- where R¹⁶ and m are as defined inclaim 29, a cis or trans- group of formula R¹⁷ OOC.CH═CH--CO-- where R¹⁷is as defined in claim 29, or a 2-, 3- or 4-pyridinecarbonyl group; R⁶and R⁷ are both hydrogen atoms; W represents a group of formula >C═NOR¹²whereR¹² represents a hydrogen atom, a group of formula --(CH₂)₃COOR^(8a), --CH₂ COOR^(8a), --C(CH₃)₂ COOR^(8a), --COCH₂ CH₂ COOR^(8a)or --CO--CH═CH--COOR^(8a) where R^(8a) is as defined in claim 29, anacetyl group, a cinnamoyl group, a benzoyl group, a pyridinecarbonylgroup or any one of the groups defined above for R³, R⁶ and R⁷ ; and nis 1 or
 2. 31. A composition as claimed in claim 29, in which:R¹, R²,R⁴, R⁵, Ar and U are as defined in claim 29; R³, R⁶ and R⁷ areindependently selected from the group consisting of C₁ -C₃ alkyl groupssubstituted by a group of formula --COOR^(8a) where R^(8a) is as definedin claim 29; W represents a group of formula >CH₂, >C═O or >C═NOR¹² ;R¹² represents a hydrogen atom, a group of formula --(CH₂)₃ COOR^(8a),--CH₂ COOR^(8a), --C(CH₃)₂ COOR^(8a), --COCH₂ CH₂ COOR^(8a) or--CO--CH═CH--COOR^(8a) where R^(8a) is as defined in claim 29, an acetylgroup, a cinnamoyl group, a benzoyl group, a pyridinecarbonyl group orany one of the groups defined above for R³, R⁶ and R⁷ ; and n is 1 or 2.32. A composition as claimed in claim 23, in which:R¹ represents analkyl group selected from the group consisting of methyl, isobutyl,hexyl, heptyl, octyl, nonyl and 3,7-dimethyloctyl groups; R² representsa hydrogen atom or a methyl group; R³ represents a hydrogen atom, a C₁-C₁₀ alkanoyl group, a C₃ -C₁₀ alkenoyl group, a C₁ -C₁₀ alkanoyl or C₃-C₁₀ alkenoyl group having at least one substituent selected from thegroup consisting of substituents (f) as defined in claim 23, anarylcarbonyl group as defined in claim 23, a group of formula R¹³--(CH₂)_(m) --CO-- of Het--CO-- where R¹³, m and Het are as defined inclaim 23 or a C₁ -C₃ alkyl group substituted by a group of formula--COOR^(8a) where R^(8a) is as defined in claim 23; R⁴ represents analkyl group selected from the group consisting of methyl, ethyl, propyl,butyl, pentyl, hexyl, heptyl, octyl, 1,1,3,3-tetramethylbutyl,1,1-dimethylbutyl and 1,1-dimethylpropyl groups; R⁵ represents ahydrogen atom or a methyl group; R⁶ represents a C₁ -C₃ alkyl groupsubstituted by a group of formula --COOR^(8a) where R^(8a) is as definedin claim 23; R⁷ represents a hydrogen atom or a C₁ -C₃ alkyl groupsubstituted by a group of formula --COOR^(8a) where R^(8a) is as definedin claim 23; Ar represents a p-phenylene group, a m-phenylene grouphaving a methyl group at the position ortho to the position ofattachment to the group of formula --(CH₂)_(n) --O-- or a pyridine-diylgroup attached to said group of formula --(CH₂)_(n) --O-- at the2-position and to the --CH₂ -thiazolidine group at the 5-position; Wrepresents a group of formula >CH₂, >C═O or >C═NOR¹², whereR¹²represents a hydrogen atom, a group of formula --(CH₂)₃ COOR^(8a), --CH₂COOR^(8a), --C(CH₃)₂ COOR^(8a), --COCH₂ CH₂ COOR^(8a) or--CO--CH═CH--COOR^(8a) where R^(8a) is as defined in claim 23, an acetylgroup, a cinnamoyl group, a benzoyl group, a pyridinecarbonyl group or aC₁ -C₃ alkyl group substituted by a group of formula --COOR^(8a) whereR^(8a) is as defined in claim 23; U represents a group of formula --CH₂--; and n is 1 or
 2. 33. A composition as claimed in claim 23, inwhich:R¹ represents an alkyl group selected from the group consisting ofhexyl, heptyl, octyl, nonyl and 3,7-dimethyloctyl groups; R² representsa hydrogen atom or a methyl group; R³ represents a hydrogen atom, a C₁-C₅ alkanoyl group, C₃ -C₅ alkenoyl group, a cinnamoyl group, a group offormula R¹⁶ OOC(CH₂)_(m) CO--where R¹⁶ represents a hydrogen atom or aC₁ -C₅ alkyl group and m is an integer from 1 to 5, a cis- or trans-group of formula R¹⁷ OOC.CH═CH--CO--where R¹⁷ represents a hydrogenatom, C₁ -C₅ alkyl group of a benzyl group, a 2-, 3- or4-pyridinecarbonyl group or a C₁ -C₃ alkyl group substituted by a groupof formula --COOR^(8a) where R^(8a) is as defined in claim 23; R⁴represents an alkyl group selected from the group consisting of methyl,ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl,1,1,3,3-tetramethylbutyl, 1,1-dimethylbutyl and 1,1-dimethylpropylgroups; R⁵ represents a hydrogen atom or a methyl group; R⁶ and R⁷ areindependently selected from the group consisting of hydrogen atoms andC₁ -C₃ alkyl groups substituted by a group of formula --COOR^(8a) whereR^(8a) is as defined in claim 23; Ar represents a p-phenylene group, am-phenylene group having a methyl group at the position ortho to theposition of attachment to the group of formula --(CH₂)_(n) --O-- or apyridine-diyl group attached to said group of formula --(CH₂)_(n) --O--at the 2-position and to the --CH₂ -thiazolidine group at the5-position; W represents a group of formula --CH₂ --, >C═O or>C═N--OR¹², whereR¹² represents a hydrogen atom, a group of formula--(CH₂)₃ COOR^(8a), --CH₂ COOR^(8a), --C(CH₃)₂ COOR^(8a), --COCH₂ CH₂COOR^(8a) or --CO--CH═CH--COOR^(8a) where R^(8a) is as defined in claim23, an acetyl group, a cinnamoyl group, a benzoyl group, apyridinecarbonyl group, a C₁ -C₅ alkyl group, a C₁ -C₅ alkyl groupsubstituted by a phenyl group where the phenyl group is unsubstituted orhas at least one substituent selected from the group consisting ofsubstituents (n), or any one of the groups defined above for R³, R⁶ andR⁷ ; said substituents (n) are selected from the group consisting of C₁-C₅ alkyl groups, C₁ -C₅ alkoxy groups and halogen atoms; and Urepresents a group of formula --CH₂ --.
 34. A composition as claimed inclaim 23, in which:R¹ represents an alkyl group selected from the groupconsisting of methyl, isobutyl, hexyl, heptyl, octyl, nonyl and3,7-dimethyloctyl groups; R² represents a hydrogen atom or a methylgroup; R³ represents a hydrogen atom, a C₁ -C₅ alkanoyl group, C₃ -C₅alkenoyl group, a cinnamoyl group, a group of formula R¹⁶ OOC(CH₂)_(m)CO--where R¹⁶ represents a hydrogen atom or a C₁ -C₅ alkyl group and mis an integer from 1 to 5, a cis- or trans- group of formula R¹⁷OOC.CH═CH--CO--where R¹⁷ represents a hydrogen atom, a C₁ -C₅ alkylgroup or a benzyl group, a 2-, 3- or 4-pyridinecarbonyl group or a C₁-C₃ alkyl group substituted by a group of formula --COOR^(8a) whereR^(8a) is as defined in claim 23; R⁴ represents an alkyl group selectedfrom the group consisting of hexyl, heptyl, octyl,1,1,3,3-tetramethylbutyl, 1,1-dimethylbutyl and 1,1-dimethylpropylgroups; R⁵ represents a hydrogen atom or a methyl group; R⁶ and R⁷ areindependently selected from the group consisting of hydrogen atoms andC₁ -C₃ alkyl groups substituted by a group of formula --COOR^(8a) whereR^(8a) is as defined in claim 23; Ar represents a p-phenylene group, am-phenylene group having a methyl group at the position ortho to theposition of attachment to the group of formula --(CH₂)_(n) --O-- or apyridine-diyl group attached to said group of formula --(CH₂)_(n) --O--at the 2-position and to the --CH₂ -thiazolidine group at the5-position; W represents a group of formula --CH₂ --, >C═O or >C═N--OR¹²whereR¹² represents a hydrogen atom, a group of formula --(CH₂)₃COOR^(8a), --CH₂ COOR^(8a), --C(CH₃)₂ COOR^(8a), --COCH₂ CH₂ COOR^(8a)or --CO--CH═CH--COOR^(8a) where R^(8a) is as defined in claim 23, anacetyl group, a cinnamoyl group, a benzoyl group, a pyridinecarbonylgroup, a C₁ -C₅ alkyl group, a C₁ -C₅ alkyl group substituted by aphenyl group where the phenyl group is unsubstituted or has at least onesubstituent selected from the group consisting of substituents (n), orany one of the groups defined above for R³, R⁶ and R⁷ ; saidsubstituents (n) are selected from the group consisting of C₁ -C₅ alkylgroups, C₁ -C₅ alkoxy groups and halogen atoms; and U represents a groupof formula --CH₂ --.
 35. A composition as claimed in claim 23, inwhich:R¹ represents an alkyl group selected from the group consisting ofmethyl, isobutyl, hexyl, heptyl, octyl, nonyl and 3,7-dimethyloctylgroups; R² represents a hydrogen atom or a methyl group; R³ representsC₁ -C₃ alkyl group substituted by a group of formula --COOR^(8a), whereR^(8a) is as defined in claim 23; R⁴ represents an alkyl group selectedfrom the group consisting of methyl, ethyl, propyl, butyl, pentyl,hexyl, heptyl, octyl, 1,1,3,3-tetramethylbutyl, 1,1-dimethylbutyl and1,1-dimethylpropyl groups; R⁵ represents a hydrogen atom or a methylgroup; R⁶ and R⁷ are both hydrogen atoms; Ar represents a p-phenylenegroup, a m-phenylene group having a methyl group at the position orthoto the position of attachment to the group of formula --(CH₂)_(n) --O--or a pyridine-diyl group attached to said group of formula --(CH₂)_(n)--O-- at the 2-position and to the --CH₂ -thiazolidine group at the5-position; W represents a group of formula --CH₂ --, >C═O, >C═N--OH, or>C═N--O--(C₁ -C₃ alkyl)--COOR^(8a) where R^(8a) is as defined in claim23; U represents a group of formula --CH₂ --; and N is 1 to
 2. 36. Acomposition as claimed in claim 23, in which:R¹ represents an alkylgroup selected from the group consisting of methyl, isobutyl, hexyl,heptyl, octyl, nonyl and 3,7-dimethyloctyl groups; R² represents ahydrogen atom or a methyl group; R³ represents --CH₂ --COO(C₁ -C₅ alkyl)group; R⁴ represents an alkyl group selected from the group consistingof methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl,1,1,3,3-tetramethylbutyl, 1,1-dimethylbutyl and 1,1-dimethylpropylgroups; R⁵ represents a hydrogen atom or a methyl group; R⁶ and R⁷ areboth hydrogen atoms; Ar represents a p-phenylene group, a m-phenylenegroup having a methyl group at the position ortho to the position ofattachment to the group of formula --(CH₂)_(n) --O-- or a pyridine-diylgroup attached to said group of formula --(CH₂)_(n) --O-- at the2-position and to the --CH₂ -thiazolidine group at the 5-position; Wrepresents a group of formula --CH₂ --, >C═O, >C═N--OH, or >C═N--O--(C₁-C₃ alkyl)--COO(C₁ -C₅ alkyl); U represents a group of formula --CH₂ --;and n is 1 to
 2. 37. A composition as claimed in claim 22, wherein saidactive compound is selected from the group consistingof:5-[4-(6-Hydroxy-5,7,8-trimethyl-2-octylchroman-2-ylmethoxy)benzyl]thiazolidine-2,4-dione;5-{4-[6-Hydroxy-4-(E)-hydroxyimino-2,5,7,8-tetramethylchroman-2-ylmethoxy]benzyl}thiazolidine-2,4-dione;5-{4-[6-Acetoxy-4-(E)-acetoxyimino-2,5,7,8-tetramethylchroman-2-ylmethoxy]benzyl}thiazolidine-2,4-dione;α-{5-[4-(6-Carboxymethoxy-2,5,7,8-tetramethyl-4-oxochroman-2-ylmethoxy)benzyl]-2,4-dioxothiazolidin-3-yl}aceticacid;α-{5-[4-(6-Carboxymethoxy-4-hydroxyimino-2,5,7,8-tetramethylchroman-2-ylmethoxy)benzyl]-2,4-dioxothiazolidin-3-yl}aceticacid;α,α'-{5-[4-(6-Carboxymethoxy-4-hydroxyimino-2,5,7,8-tetramethylchroman-2-ylmethoxy)benzyl]-2,4-dioxothiazolidine-3,5-diyl}diaceticacid; and pharmaceutically acceptable salts thereof.